Productioin of dolasetron

ABSTRACT

The present invention provides an improved process for the preparation of Dolasetron salts, in particularly Dolasetron mesylate. Also provided are intermediates for the process and methods of preparing the intermediates. Intermediates for preparing Dolasetron according to the invention include 7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo[3.3.1]nonane compounds (SAN compounds) and endo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0 3,8 ]undecan-10-one compounds (SQO compounds).

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of the following U.S.Provisional Patent Application No. 60/756,690, filed Jan. 5, 2006;60/800,884, filed May 15, 2006; 60/838,758, filed Aug. 17, 2006;60/861,354, filed Nov. 27, 2006; 60/802,842, filed May 22, 2006;60/818,934, filed Jul. 5, 2006; 60/833,515, filed Jul. 24, 2006;60/836,432, filed Aug. 7, 2006; 60/763,683, filed Jan. 30, 2006;60/784,248, filed Mar. 20, 2006; 60/815,199, filed Jun. 19, 2006;60/852,887, filed October 18, 2006. The contents of these applicationsare incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparationof Dolasetron salts, in particularly Dolasetron mesylate, andintermediates thereof.

BACKGROUND OF THE INVENTION

Dolasetron mesylate monohydrate,(2′,6α,8α,9αβ)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1H-indole-3-carboxylatemonomethanesulfonate monohydrate, (referred to as DLS-MsOH—H₂O) acompound having the chemical structure,

Dolasetron Mesylate Monohydrate

is a serotonin receptor (5-HT₃) antagonist used as an antiemetic andantinauseant agent in chemo- and radiotherapies.

DLS-MsOH-H₂O developed by Merrell Dow Pharmaceuticals is marketed astablets for oral administration and as sterile solution for intravenousadministration by Aventis, under the name Anzemet®.

DLS-MsOH and its monohydrate form can be prepared by a multi stepsynthesis, as described in EP patent No. 0339669 (“the EP '669 patent”)as illustrated in the following scheme

Accordingly, step (c) of the reaction involves oxidation with a molarequivalent of an expensive oxidizing reagent, 3-chloroperbenzoic acid(referred to as mCPBA), which transforms to 3-chlorobenzoic acid(referred to as mCBA), waste that is disposed at the end of thereaction. Removal of mCBA is problematic, hence, leading to acontaminated product. CCA-epoxide is also contaminated by other aromaticimpurities, such as [(3-ClPh)C(O)O]₂ (the corresponding peroxide ) in anamount of 5%. Therefore, the oxidation reaction as described above isnon-economic for scale-up. Also, the reaction in steps (e) and (f) aredone by using periodic acid in ethyl acetate in step (e), and water as asolvent in step (f). Since, the reagents and the reduction products havelow solubility in ethylacetate; the reaction disclosed in the abovepatent is slower. Also, the reaction in ethylacetate is more dangerous.In addition, since two different solvents are used in steps (e) and (f),a work-up procedure, which can lead to a decomposition of the sensitive3-methoxycarbonyl-1,5-glutardialdehyde (the product of the oxidationstep), is required.

A similar process is apparently described in EP patent No. 0266730,comprising an oxidation reaction, as described in step (c) of the abovescheme, to the corresponding diol, instead of to the epoxide, asapparently disclosed in EP patent No. 0339669. The diol is thentransformed to DLS-base in a similar way.

Hence, there is a need in the art for an improved process for thepreparation of Dolasetron salts, preferably, Dolasetron Mesylate.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a quaternary ammoniumsalt of a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-onecompound (referred to as an OAN compound salt) of formula Vs;

wherein R₁ and R₂ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl,preferably, a C₁₋₄ alkyl, more preferably, methyl, and Z is an acid,preferably, methanesulfonic acid.

In another embodiment, the present invention provides crystallinemethanesulfonate salt of7-methoxycarbonyl-9-(methoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-one(referred to as OAN-MsOH).

In yet another embodiment, the present invention provides a quaternaryammonium salt of a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane3-olcompound (referred to as a HAN compound salt) of formula VIs;

wherein R₁, R₂ and Z are described before.

In one embodiment, the present invention provides crystallinemethanesulfonate salt of7-methoxycarbonyl-9-(methoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane3-ol(referred to as HAN-MsOH).

In yet another embodiment, the present invention provides a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo[3.3.1]nonanecompound (referred to as a SAN compound) of formula X;

wherein R₁ and R₂ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl,preferably, a C₁₋₄ alkyl, more preferably, methyl, and R₃R₄R₅ areindependently a C₁₋₆ alkyl or a C₆₋₈ aryl, or together are atert-butyldialkyl, preferably, tert-butyldimethyl.

In one embodiment, the present invention provides anendo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-one(trans-hexahydro-4-alkoxycarbonyl-8-trialkylsilyloxy-2,6-methano-2H-quinolizin-3(4H)-one)compound (referred to as a SQO compound) of formula XII

wherein R is a C₁₋₆ alkyl or a C₆₋₈ aryl, preferably, a C₁₋₄ alkyl, morepreferably, methyl, and R₃R₄R₅ are independently a C₁₋₆ alkyl or a C₆₋₈aryl, or together are a tert-butyldialkyl, preferably,tert-butyldimethyl.

In another embodiment, the present invention provides crystallineendo-9-methoxycarbonyl-5-tert-butyldimethylsilyloxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-one(trans-hexahydro-4-methoxycarbonyl-8-tert-butyldimethylsilyloxy-2,6-methano-2H-quinolizin-3(4H)-one)(referred to as SQO).

In yet another embodiment, the present invention provides a quaternaryammonium salt ofendo-5-hydroxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-one(trans-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one)(referred to as a HQO-salt) of formula IIs;

wherein Y is an acid selected from the group consisting of hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid,fluoroboric acid, formic acid, acetic acid, propionic acid,trichloroacetic acid, trifluoroacetic acid, maleic acid, fumaric acid,succinic acid, oxalic acid, tartaric acid, citric acid, mandelic acid,benzoic acid, salicylic acid, naphthalene carboxylic and dicarboxylicacids, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonicacid, naphthalene sulfonic and disulfonic acids.

In one embodiment, the present invention provides a process for thepreparation of a CCA-epoxide of formula IV

comprising combining a CCA-ester of formula III,

an oxidizing agent selected from a group consisting of hydroperoxide,dialkyl peroxide, peroxyacid, peroxyester, diacyl peroxide, persulphate,perborate, and perphosphate, a catalyst, and a solvent selected from thegroup consisting of water, a water miscible organic solvent, andmixtures thereof, to obtain a CCA-epoxide of formula IV; wherein, R₁ isC₁₋₆ alkyl or C₆₋₈ aryl, preferably, C₁₋₄ alkyl, more preferably,methyl.

In another embodiment, the present invention provides a process for thepreparation of a DLS-salt of formula VIIIs,

comprising preparing a CCA-epoxide of formula IV by the process of theinvention; and converting it to a DLS-salt of formula VIIIs, wherein Xis an acid selected from the group consisting of: hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,perchloric acid, fluoroboric acid, formic acid, acetic acid, propionicacid, trichloroacetic acetic, trifluoroacetic acid, maleic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, citric acid, mandelicacid, benzoic acid, salicylic acid, naphthalene carboxylic anddicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, benzenesulfonic acid, naphthalene sulfonic and disulfonic acids,preferably, methane sulfonic acid.

In yet another embodiment, the present invention provides a process forthe preparation of an OAN compound of formula V

comprising combining a CCA-epoxide of formula IV, an oxidizing agent,and a solvent selected from the group consisting of water, a watermiscible organic solvent, and mixtures thereof, to form a reactionmixture; raising the pH of the reaction mixture; and adding to theresulting product a pH 4 buffer, a glycine C₁₋₄ ester or salts thereof,and a substance comprising a carbonyl moiety selected from the groupconsisting of 1,3-acetonedicarboxylic acids, acetone and C₁₋₄ estersthereof, to form an OAN compound of formula V, wherein R₁ and R₂ areindependently, C₁₋₆ alkyl or C₆₋₈ aryl, preferably, C₁₋₄ alkyl, morepreferably, methyl.

In one embodiment, the present invention provides a process for the 10preparation of a DLS-salt of formula VIIIs, comprising preparing an OANcompound of formula V by the process of the invention; and converting itto a DLS-salt of formula VIIIs.

In another embodiment, the present invention provides a process for thepreparation of an OAN compound salt of formula Vs

comprising combining an OAN compound of formula V, an acid, and anorganic solvent selected from the group consisting of a C₁₋₄ alcohol, aC₂₋₈ ester, a linear, branched or cyclic C₂₋₈ ether, a C₃₋₆ ketone, aC₅₋₈ aliphatic hydrocarbon, a C₁₋₈ halogenated hydrocarbon, a C₁₋₄nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈ aromatic hydrocarbon, a C₃₋₁₀amide, and mixtures thereof to form an OAN salt; wherein R₁ and R₂ areindependently, C₁₋₆ alkyl or C₆₋₈ aryl, preferably, C₁₋₄ alkyl, morepreferably, methyl, and Z is an acid, preferably, methanesulfonic acid.

In yet another embodiment, the present invention provides a process forpurifying an OAN compound of formula V comprising combining an OANcompound of formula V, an acid, and an organic solvent selected from thegroup consisting of a C₁₋₄ alcohol, a C₂₋₈ ester, a linear, branched orcyclic C₂₋₈ ether, a C₃₋₆ ketone, a C₅₋₈ aliphatic hydrocarbon, a C₁₋₈halogenated hydrocarbon, a C₁₋₄ nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈aromatic hydrocarbon, a C₃₋₁₀ amide, and mixtures thereof; and adding abase to obtain a purified OAN compound.

In one embodiment, the present invention provides a process for thepreparation of a DLS-salt of formula VIIIs comprising preparing an OANcompound salt of formula Vs by the process of the invention, andconverting it to a DLS-salt of formula VIIIs.

In another embodiment, the present invention provides a process for thepreparation of a HAN compound of formula VI

comprising combining an OAN compound salt of formula Vs, a reducingagent, and a solvent selected from the group consisting of water, watermiscible organic solvents and mixtures thereof, forming a HAN compoundof formula VI.

In yet another embodiment, the present invention provides a process forthe preparation of a HAN compound salt of formula VIs

comprising combining a HAN compound of formula VI,

an acid, and an organic solvent selected from the group consisting of aC₁₋₄ alcohol, a C₂₋₈ ester, a linear, branched or cyclic C₂₋₈ ether, aC₃₋₆ ketone, a C₅₋₈ aliphatic hydrocarbon, a C₁₋₈ halogenatedhydrocarbon, a C₁₋₄ nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈ aromatichydrocarbon, a C₃₋₁₀ amide and mixtures thereof, forming a HAN salt,wherein, Z is an acid, preferably methanesulfonic acid, R₁ and R₂ areindependently, C₁₋₆ alkyl or C₆₋₈ aryl, preferably, C₁₋₄ alkyl, morepreferably, methyl.

In yet another embodiment, the present invention provides a process forthe preparation of a DLS-salt of formula VIIIs comprising preparing aHAN compound of formula VI by the process of the invention, andconverting it to a DLS-salt of formula VIIIs.

In one embodiment, the present invention provides a process forpurifying a HAN compound of formula VI comprising combining a HANcompound of formula VI, an acid, and an organic solvent selected fromthe group consisting of a C₁₋₄ alcohol, a C₂₋₈ ester, a linear, branchedor cyclic C₂₋₈ ether, a C₃₋₆ ketone, a C₅₋₈ aliphatic hydrocarbon, aC₁₋₈ halogenated hydrocarbon, a C₁₋₄ nitroalkane, a C₁₋₄ alkylcyanide, aC₆₋₈ aromatic hydrocarbon, a C₃₋₁₀ amide, and mixtures thereof; andadding a base to obtain a purified HAN compound.

In another embodiment, the present invention provides a process for thepreparation of a DLS-salt of formula VIIIs comprising preparing a HANcompound salt of formula VIs by the process of the invention, andconverting it to a DLS-salt of form.

In yet another embodiment, the present invention provides a process forthe preparation of a SAN compound of formula X

comprising combining a HAN-salt of formula VIs

a silylating agent selected from a group consisting of: silanes, silylhalogenides, silyl cyanides, silyl amines, silyl amides, silyltrifluoromethanesulfonates (silyl triflates), and silazanes, a base, andan aprotic organic solvent to obtain the SAN compound of formula X,wherein R₁ and R₂ are independently, C₁₋₆ alkyl or C₆₋₈ aryl,preferably, C₁₋₄ alkyl, more preferably methyl, R₃R₄R₅ are independentlya C₁₋₆ alkyl or a C₆₋₈ aryl, or together are a tert-butyldialkyl,preferably tert-butyldimethyl, and Z is an acid, preferablymethanesulfonic acid.

In one embodiment, the present invention provides a process for thepreparation of a DLS-salt of formula VIIIs, comprising preparing a SANcompound of formula X by the process of the invention, and converting itto a DLS-salt of formula VIIIs.

In another embodiment, the present invention also provides a process forthe preparation a SQO compound of formula XII

comprising mixing a SAN compound of formula X, a metal alkoxide, and apolar aprotic organic solvent to form a mixture; heating the mixture;and reacting it with a weak acid forming the SQO compound of formulaXII, wherein, R is a C₁₋₆ alkyl or C₆₋₈ aryl, preferably a C₁₋₄ alkyl,more preferably methyl, and R₃R₄R₅ are independently a C₁₋₆ alkyl or aC₆₋₈ aryl, or together are a tert-butyldialkyl, preferably,tert-butyldimethyl.

In yet another embodiment, the present invention provides a process forthe preparation of a DLS-salt of formula VIIIs, comprising preparing aSQO compound of formula XII by the process of the invention, andconverting it to a DLS-salt of formula VIIIs.

In one embodiment, the present invention also provides a process forpreparing HQO of formula II

comprising mixing a SQO compound of formula XII, water and an acidselected from the group consisting of hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid,fluoroboric acid, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, benzenesulfonic acid, naphthalene sulfonic and disulfonic acids toobtain HQO of formula II.

In another embodiment, the present invention further provides a processfor the preparation of a DLS-salt of formula VIIIs, comprising preparingHQO of formula II by the process of the invention, and converting it toa DLS-salt of formula VIIIs.

In yet another embodiment, the present invention provides anotherprocess for the preparation of a HQO-salt of formula IIs comprisingcombining HQO, an alcohol and an acid selected from the group consistingof: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, perchloric acid, fluoroboric acid, formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, maleicacid, fumaric acid, succinic acid, oxalic acid, tartaric acid, citricacid, mandelic acid, benzoic acid, salicylic acid, naphthalenecarboxylic and dicarboxylic acids, methanesulfonic acid, ethanesulfonicacid, trifluoromethanesulfonic acid, p-toluenesulfonic acid,benzenesulfonic acid, naphthalene sulfonic, and disulfonic acids,forming a HQO salt of formula IIs.

In one embodiment, the present invention provides a process forpurifying HQO of formula II comprising a) combining HQO of formula II,an alcohol and an acid selected from the group consisting of:hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, perchloric acid, fluoroboric acid, formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, maleicacid, fumaric acid, succinic acid, oxalic acid, tartaric acid, citricacid, mandelic acid, benzoic acid, salicylic acid, naphthalenecarboxylic and dicarboxylic acids, methanesulfonic acid, ethanesulfonicacid, trifluoromethanesulfonic acid, p-toluenesulfonic acid,benzenesulfonic acid, naphthalene sulfonic, and disulfonic acids; and b)adding a base, to obtain a purified HQO of formula II.

In one embodiment, the present invention provides a process for thepreparation of a DLS-salt of formula VIIIs, comprising preparing aHQO-salt of formula IIs by the process of the invention, and convertingit to a DLS-salt of formula VIIIs.

In yet another embodiment, the present invention provides a process forthe preparation of a DLS-salt of formula VIIIs, comprising the steps ofa) combining a CCA-ester of formula III, an oxidizing agent selectedfrom the group consisting of: hydroperoxides, dialkyl peroxides,peroxyacids, peroxyesters, diacyl peroxides, persulphate, perborate andperphosphate, a catalyst and a solvent selected from the groupconsisting of water, water miscible organic solvents and mixturesthereof, to form a first intermediate mixture; b) adding to the firstintermediate mixture an oxidizing agent, and a solvent selected from thegroup consisting of water and a water miscible organic solvent, to forma second intermediate mixture; c) raising the pH of the secondintermediate mixture; d) reacting the products in the second reactionmixture with a pH 4 buffer, a glycine C₁₋₄ ester or salts thereof, and asubstance comprising a carbonyl moiety selected from the groupconsisting of 1,3 acetonedicarboxylic acids, acetone and a C₁₋₄ esterthereof, to form a third reaction mixture; e) adding to the thirdintermediate mixture a reducing agent, and a solvent selected from thegroup consisting of water, water miscible organic solvents and mixturesthereof, to form a fourth intermediate mixture; f) adding to the fourthintermediate mixture a silylating agent selected from a group consistingof: silanes, silyl halogenides, silyl cyanides, silyl amines, silylamides, silyl trifluoromethanesulfonates (silyl triflates), andsilazanes, a base, and an aprotic organic solvent to form a fifthintermediate mixture; g) adding to the fifth intermediate mixture ametal alkoxide, and a polar aprotic organic solvent to form a sixthintermediate mixture; h) heating the sixth intermediate mixture; i)reacting the products in the sixth intermediate mixture with a weak acidforming a seventh intermediate mixture; j) adding to the seventhintermediate mixture water and an acid to form an eight intermediatemixture; k) mixing the eight intermediate mixture with an anhydride,3-indole carboxylic acid, a halogenated hydrocarbon, and a catalyst;and 1) reacting the product from step k) with an acid to obtain theDLS-salt of formula VIIIs.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates powder X-ray diffraction pattern for OAN-MsOH.

FIG. 2 illustrates powder X-ray diffraction pattern for HAN-MsOH.

FIG. 3 illustrates powder X-ray diffraction pattern for SQO.

FIG. 4 illustrates powder X-ray diffraction pattern for HQO-HCl.

FIG. 5 illustrates powder X-ray diffraction pattern for HQO-CSA.

FIG. 6 illustrates powder X-ray diffraction pattern for HQO-base.

DETAILED DESCRIPTION OF THE INVENTION

The present invention offers novel intermediates in the syntheses ofDolasetron salts, and processes for preparing them. The invention alsooffers the use of these intermediates in novel processes for preparingDolasetron salts, especially, the mesylate salt.

The present invention provides a process for the preparation of aDLS-salt of formula VIIIs, comprising the steps of a) combining aCCA-ester of formula III, an oxidizing agent selected from the groupconsisting of: hydroperoxides, dialkyl peroxides, peroxyacids,peroxyesters, diacyl peroxides, persulphate, perborate and perphosphate,a catalyst and a solvent selected from the group consisting of water,water miscible organic solvents and mixtures thereof, to formCCA-epoxide of formula IV; b) admixing CCA-epoxide with an oxidizingagent, and a solvent selected from the group consisting of water and awater miscible organic solvent; c) raising the pH of the mixture; d)admixing the mixture with a pH 4 buffer, a glycine C₁₋₄ ester or saltsthereof, and a substance comprising a carbonyl moiety selected from thegroup consisting of 1,3 acetonedicarboxylic acids, acetone and a C₁₋₄ester thereof, to form OAN of formula V; e) admixing the material of theprevious step with a reducing agent, and a solvent selected from thegroup consisting of water, water miscible organic solvents and mixturesthereof, to form HAN of formula VI; f) admixing the material of theprevious step with a silylating agent selected from a group consistingof: silanes, silyl halogenides, silyl cyanides, silyl amines, silylamides, silyl trifluoromethanesulfonates (silyl triflates), andsilazanes, a base, and an aprotic organic solvent to form SAN of formulaX; g) admixing the material of the previous step with a metal alkoxide,and a polar a-protic organic solvent to form a reaction mixture; h)heating the reaction mixture; i) quenching the reaction mixture with awith a weak acid forming SQO of formula XII; j) admixing the material ofthe previous step with a solvent selected from a group consisting of:water, and water-immiscible organic solvent, and an acid to form HQO offormula II; k) admixing the material of the previous step with ananhydride, 3-indole carboxylic acid, a halogenated hydrocarbon, and acatalyst to obtain Dolasetron base; and 1) reacting Dolasetron base withan acid to obtain the DLS-salt of formula VIIIs. Preferably, the weakacid in step i) is selected from the group consisting of acetic acid,formic acid, acetic acid, propionic acid, maleic acid, fumaric acid,succinic acid, oxalic acid, tartaric acid, citric acid, mandelic acid,benzoic acid, and salicylic acid. Preferably, the acid in step j) isselected from the group consisting of hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid,fluoroboric acid, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, benzenesulfonic acid, naphthalene sulfonic and disulfonic acids.Preferably, the acid in step l) is selected from the group consisting ofhydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, perchloric acid, fluoroboric acid, formic acid, aceticacid, propionic acid, trichloroacetic acetic, trifluoroacetic acid,maleic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid,citric acid, mandelic acid, benzoic acid, salicylic acid, naphthalenecarboxylic and dicarboxylic acids, methanesulfonic acid, ethanesulfonicacid, trifluoromethanesulfonic acid, p-toluenesulfonic acid,camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic anddisulfonic acids, preferably, methane sulfonic acid. In the alternative,the weak acid in step i) can be a (strong) acid as in step j), in whichinstant the step j) of this process may be omitted.

The process can be illustrated by the following scheme:

The present invention provides a quaternary ammonium salt of a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-onecompound (referred to as an OAN-salt) of formula Vs;

wherein R₁ and R₂ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl,preferably, a C₁₋₄ alkyl, more preferably, methyl, and Z is an acid,preferably, methanesulfonic acid.

When R₁ and R₂ are methyl, and Z is methanesulfonic acid, said compoundof formula Vs refers to the methanesulfonate salt of7-methoxycarbonyl-9-(methoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-one(referred to as OAN-MsOH) of the following formula.

The present invention further provides crystalline OAN-MsOH. Thecrystalline OAN-MsOH of the present invention may be characterized by apowder XRD diffraction pattern having peaks at about 8.5, 18.0, and 20.9degrees two-theta, ±0.2 degrees two-theta. Crystalline OAN-MsOH may befurther characterized by a powder XRD diffraction pattern having peaksat about 14.7, 22.7, 24.3, 25.0, 26.3 and 27.9 degrees two-theta, ±0.2degrees two-theta. Crystalline OAN-MsOH may be also substantiallyidentified by the PXRD pattern as depicted in FIG. 1.

The present invention also provides a quaternary ammonium salt of a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane3-olcompound (referred to as a HAN-salt) of formula VIs;

wherein R₁, R₂ and Z are described before.

When R₁ and R₂ are methyl, and Z is methanesulfonic acid, said compoundof formula VIs refers to the methanesulfonate salt of7-methoxycarbonyl-9-(methoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane3-ol(referred to as HAN-25 MsOH) of the following formula.

The present invention provides crystalline HAN-MsOH. The crystallineHAN-MsOH of the present invention may be characterized by a powder XRDdiffraction pattern having peaks at about 7.3, 11.6, and 14.6 degreestwo-theta, ±0.2 degrees two-theta. The crystalline HAN-MsOH may befurther characterized by a powder XRD diffraction pattern having peaksat about 15.9, 17.9, 19.0, 20.4, 21.9, 29.0 and 29.4 degrees two-theta,±0.2 degrees two-theta. The crystalline HAN-MsOH may be alsosubstantially identified by the PXRD pattern as depicted in FIG. 2.

The present invention further provides a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo[3.3.1]nonanecompound (referred to as a SAN compound) of formula X;

wherein R₁ and R₂ are described before.

When R₁ and R₂ are methyl, and R₃R₄R₅ is tert-butyldimethyl, saidcompound of formula X refers to7-methoxycarbonyl-9-(methoxycarbonylmethyl)-3-tert-butyldimethylsilyloxy-9-azabicyclo[3.3.1]nonane(referred to as SAN) of the following formula.

The present invention also provides anendo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-one(trans-hexahydro-4-alkoxycarbonyl-8-trialkylsilyloxy-2,6-methano-2H-quinolizin-3(4H)-one)compound (referred to as a SQO compound) of formula XII

wherein R is a C₁₋₆ alkyl or a C₆₋₈ aryl, preferably, a C₁₋₄ alkyl, morepreferably, methyl, and R₃R₄R₅ are independently a C₁₋₆ alkyl or a C₆₋₈aryl, preferably, tert-butyldialkyl, more preferably,tert-butyldimethyl.

Preferably, when R is methyl and R₃R₄R₅ is tert-butyldimethyl, saidcompound of formula XII refers toendo-9-methoxycarbonyl-5-tert-butyldimethylsilyloxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-one(trans-hexahydro-4-methoxycarbonyl-8-tert-butyldimethylsilyloxy-2,6-methano-2H-quinolizin-3(4H)-one)(referred to as SQO) of the following formula.

The present invention provides crystalline SQO. The crystalline SQO ofthe present invention may be characterized by an XRD diffraction patternhaving peaks at about 5.1, 10.1, 12.7, and 20.3 degrees two-theta, ±0.2degrees two-theta. The crystalline SQO may be further characterized byan XRD diffraction pattern having peaks at about 15.2, 17.0, 17.6, 18.3,19.1, and 19.8 degrees two-theta, ±0.2 degrees two-theta. Thecrystalline SQO may be also substantially identified by the PXRD patternas depicted in FIG. 3.

The present invention further provides a quaternary ammonium salt ofendo-5-hydroxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-one(trans-hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3(4H)-one)(referred to as a HQO-salt) of formula IIs;

wherein Y is an acid selected from the group consisting of: hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,perchloric acid, fluoroboric acid, formic acid, acetic acid, propionicacid, trichloroacetic acetic, trifluoroacetic acid, maleic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, citric acid, mandelicacid, benzoic acid, salicylic acid, naphthalene carboxylic anddicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonicacid, naphthalene sulfonic and disulfonic acids, preferably,methanesulfonic acid.

Preferably, when Y is HCl, said HQO-salt of formula IIs corresponds toHQO-HCl of the following formula.

The present invention provides crystalline HQO-HCl salt. The crystallineHQO-HCl salt of the present invention may be characterized by a powderXRD diffraction pattern as depicted in FIG. 4.

The present invention also provides a process for the preparation of aCCA-epoxide of formula IV

comprising combining a CCA-ester of formula III,

an oxidizing agent selected from the group consisting of: ahydroperoxide, a dialkyl peroxide, a peroxyacid, a peroxyester, a diacylperoxide, a persulphate, a perborate, a perphosphate, and adimethyldioxiran, a catalyst, and a solvent selected from the groupconsisting of water, water miscible organic solvents, and mixturesthereof, to obtain the CCA-epoxide of formula IV, wherein R₁ is a C₁₋₆alkyl or a C₆₋₈ aryl, preferably, a C₁₋₄ alkyl, more preferably, methyl.

When R₁ is methyl, said CCA-ester of formula III corresponds toCCA-methylester of the following formula,

and said CCA-epoxide of formula IV corresponds to CCA-epoxide of thefollowing formula.

Preferably, the CCA-ester of formula III is combined with a solventselected from the group consisting of water, water miscible organicsolvents, and mixtures thereof, to obtain a solution.

Preferably, the water miscible organic solvent is selected from thegroup consisting of linear or branched C₁₋₄ alcohols. Preferably, theC₁₋₄ alcohol is a C₁₋₃ alcohol, more preferably, a C₁₋₂ alcohol, mostpreferably, methanol. In the alternative, a mixture of water and a waterimmiscible organic solvent may be used in the presence of a phasetransfer catalyst. Preferably, the water immiscible organic solvent isselected from the group consisting of a C₁₋₈ halogenated hydrocarbon, aC₂₋₈ ester, a C₂₋₈ ether and a C₃₋₆ ketone. A preferred C₁₋₈ halogenatedhydrocarbon is a C₁₋₄ halogenated hydrocarbon, more preferably a C₁₋₂halogenated hydrocarbon. Preferably, the C₁₋₂ halogenated hydrocarbon isdichloromethane, 1,2-dichloroethane or chloroform, more preferablydichloromethane. A preferred C₂₋₈ ester is a C₂₋₆ ester, morepreferably, a C₄₋₆ ester. Preferably, the C₄₋₆ ester is ethyl acetate,n-butyl acetate or isobutyl acetate, more preferably ethyl acetate. Apreferred C₂₋₈ ether is a C₂₋₆ ether, more preferably, a C₄₋₆ ether.Preferably, the C₄₋₆ ether is diethyl ether, diisopropyl ether ortert-butyl methyl ether, more preferably tert-butyl methyl ether. Apreferred C₃₋₆ ketone is a C₄₋₆ ketone. Preferably, the C₄₋₆ ketone ismethyl ethyl ketone (2-butanone), 2-pentanone, 3-pentanone or3,3-dimethyl-2-butanone, more preferably 2-pentanone. The most preferredsolvent is dichloromethane. Further, the phase transfer catalyst ispreferably a quaternary ammonium salt, more preferably the phasetransfer catalyst is tetrabutyl ammonium bromide.

Preferably, the solution is combined with an oxidizing agent selectedfrom the group consisting of: a hydroperoxide, a dialkyl peroxide, aperoxyacid, a peroxyester, a diacyl peroxide, a persulphate, aperborate, a perphosphate, and a dimethyldioxiran, and a catalyst, toobtain a mixture.

Preferably, the hydroperoxide is RO—OH, wherein R is either H or analkyl group. Preferably, the alkyl group is a C₁₋₆ alkyl, morepreferably t-butyl. A preferred dialkyl peroxide is RO—OR, wherein R isa C₁₋₆ alkyl, preferably t-butyl. Preferably, the peroxyacid isRCO—O—OH. More preferably, the RCO—O—OH is selected from the groupconsisting of: peracetic acid, trifluoroperacetic acid, perlauric acid,perbenzoic acid, and 3,5-dinitroperbenzoic acid. Preferably, theperoxyester is RCO—O—OR′, wherein R is phenyl or methyl, and R′ is anC₁₋₆ alkyl, preferably t-butyl. A preferred diacyl peroxide isRCO—O—O—COR, wherein R is phenyl or methyl. A preferred persulphate isperoxydisulphuric acid (M₂S₂O₈) in the form of a potassium, sodium orammonium (M=K, Na, NH₄) salt, peroxymonosulfuric acid (Caro's acid), andOxone® (potassium monopersulfate triple salt: KHSO₅—KHSO₄—K₂SO₄(2:1:1)”). The more preferred oxidizing agent is hydroperoxide, mostpreferably, hydrogen peroxide. Preferably, an aqueous solution ofhydrogen peroxide is used. A preferred concentration of the solution isof about 3% to about 50%, more preferably of about 20% to about 40%,most preferably of about 30% to about 35%.

Preferably, the catalyst is selected from the group consisting ofZeolites and polyoxometalates. Preferably, the metal moiety of thepolyoxometalates is selected from the group consisting of tungsten,molybdenum, rhenium, vanadium and niobium. More preferably, the catalystis either sodium tungstate dihydrate or sodium molybdenate dihydrate.

A preferred amount of the catalyst is about 0.01 mole % to about 50 mole% per mole of the CCA-ester, more preferably about 1 mole % to about 10mole % per mole of the CCA-ester, most preferably about 2 mole % permole of the CCA-ester.

In preparing the CCA epoxide of formula IV, the reaction mixture ismaintained at a temperature of about 0° C. to about 80° C., preferablyabout 30° C. to about 80° C., more preferably, at a temperature of about15° C. to about 65° C., most preferably at a temperature of about 60° C.to about 65° C. The reaction mixture is preferably, maintained at suchtemperature for a period of about 0.5 hours to about 24 hours, morepreferably for about 1 to about 10 hours, most preferably for about 2hours to about 4 hours.

The progress of the reaction may be monitored by gas-chromatography(referred to as GC) or by thin-layer chromatography (referred to asTLC). When monitored by TLC, an eluent of n-hexane and ethylacetate in aratio of 1:1 may be used.

The process for preparing a CCA-ester of formula IV may further comprisea recovery step. The CCA-epoxide of formula IV may be recoveredcomprising the steps of adjusting the temperature of the reactionmixture to a temperature of about 20° C. to about 30° C.; extracting theproduct with a water immiscible organic solvent, preferably,dichloromethane; and evaporating the solvent.

The process for preparing a CCA-ester of formula IV may further comprisea process for converting it to a DLS-salt of formula VIIIs,

wherein, X is an acid selected from the group consisting of:hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, perchloric acid, fluoroboric acid, formic acid, aceticacid, propionic acid, trichloroacetic acetic, trifluoroacetic acid,maleic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid,citric acid, mandelic acid, benzoic acid, salicylic acid, naphthalenecarboxylic and dicarboxylic acids, methanesulfonic acid, ethanesulfonicacid, trifluoromethanesulfonic acid, p-toluenesulfonic acid,camphorsulfonic acid, benzenesulfonic acid, naphthalene sulfonic anddisulfonic acids, preferably, methane sulfonic acid. This conversion toa DLS salt of formula VIIIs may be carried out by the process of theinvention or any other known process converting the CCA epoxide offormula IV to a DLS salt of formula VIIIs as described for example in EP0339699, example 9.

When X is methane sulfonic acid, said DLS-salt of formula VIIIscorresponds to DLS-MsOH of the following formula.

The process of the present invention provides an OAN compound of formulaV prepared by a process comprising an oxidation reaction followed byRobinson-Schöpf reaction, wherein both reactions are done in water, andtherefore can be done concurrently, i.e., without isolation of theoxidation product, prior to the Robinson-Schöpf reaction. The oxidationapplies the use of periodic acid in water, in which the reagents and thereduction products have high solubility; hence, the reaction is fast.Also, using water allows controlling the exothermic nature of thereaction, thus, reducing the danger.

The present invention further provides a process for the preparation ofan OAN compound of formula V

comprising combining a) a CCA-epoxide of formula IV, an oxidizing agent,and a solvent selected from the group consisting of water, watermiscible organic solvents, and mixtures thereof, to form a reactionmixture; b) raising the pH of the reaction mixture; c) and adding to thereaction mixture of step b) a pH 4 buffer, glycine C₁₋₄ ester or saltsthereof, and a substance comprising carbonyl moiety selected from thegroup consisting of 1,3-acetonedicarboxylic acid, acetone and a C₁₋₄ester thereof, to form the OAN compound of formula V, wherein R₁ and R₂are independently a C₁₋₆ alkyl or a C₆₋₈ aryl, preferably, a C₁₋₄ alkyl,more preferably, methyl.

When R₁ and R₂ are methyl, said OAN compound of formula V corresponds toOAN of the following formula.

Combining a CCA-epoxide of formula IV, an oxidizing agent, and a solventselected from the group consisting of water, water miscible organicsolvents, and mixtures thereof, to form a reaction mixture; and raisingthe pH of the reaction mixture, may be designated as an oxidationreaction.

Preferably, combining a CCA-epoxide of formula IV with an oxidizingagent, and a solvent selected from the group consisting of water, watermiscible organic solvent and mixtures thereof provides a first reactionmixture.

Preferably, the water miscible organic solvent is selected from thegroup consisting of: a nitrile, a ketone and an ether. A preferrednitrile is a C₂₋₄ nitrile. Preferably, the C₂₋₄ nitrile is acetonitrile,propionitrile or butyronitrile. A preferred ketone is a C₃₋₆ ketone.Preferably, the C₃₋₆ ketone is acetone, methyl ethyl ketone or diethylketone. Preferably, the ether is a cyclic ether. A preferred cyclicether is THF, 1,4-dioxane or 1,3-dioxolane. The preferred solvent iswater.

Preferably, the oxidizing agent is selected from the group consistingof: periodic acid and salts thereof, lead tetraacetate, cerium andammonium nitrate (Ce(NH₄)₂(NO₃)₆). More preferably, the oxidizing agentis periodic acid. Preferably, the oxidizing agent is added in the formof a solution when the solvent is water.

Preferably, the first reaction mixture is maintained at a temperature ofabout 10° C. to about 60° C., more preferably at a temperature of about10° C. to about 15° C. Preferably, the first mixture is maintained for aperiod of about 0.5 hours to about 24 hours, and more preferably forabout 1 to about 3 hours. Maintaining the first reaction mixture ispreferably done while stirring.

The first reaction mixture is, preferably, acidic. Preferably, the pH ofthe acidic first reaction mixture is of about 0.5 to about 7, morepreferably of about 0.5 to about 2.

Preferably, the pH of the maintained first reaction mixture is increasedto about 2 to about 7. The pH is raised, preferably to about 3.5 toabout 4.5. Preferably, the pH is raised by using a water immisciblebase, more preferably either poly(4-vinylpyridine) or OH resins, andeven more preferably, OH resins. The water immiscible base is,preferably, filtered off, more preferably through Celite, providing anaqueous solution of the product of the oxidation reaction. Preferably,adjusting the pH is performed at a temperature of about 15° C. to about35° C., more preferably at about room temperature.

The reaction may be run stepwise or concurrently, i.e., withoutisolation of the oxidation product prior to the Robinson-Schöpfreaction. Preferably, the process is run concurrently.

Preferably, after adjusting the pH, a pH 4 buffer, a glycine C₁₋₄ esteror salts thereof, and a substance comprising carbonyl moiety selectedfrom the group consisting of a 1,3-acetonedicarboxylic acids, acetoneand C₁₋₄ esters thereof, are added to obtain a second reaction mixture.

Preferably, the pH 4 buffer is an amine-free buffer. Preferably, theamine-free buffer is selected from the group consisting of: a citricacid-sodium hydroxide-hydrochloric acid buffer, a citric acid-disodiumhydrogenphosphate buffer, a sodium acetate-acetic acid buffer, apotassium diphthalate-sodium hydroxide buffer, sodium dihydrogenphosphate and potassium hydrogen phthalate. More preferably, theamine-free buffer is potassium hydrogen phthalate. Preferably, thebuffer is used in an amount of about 1 to about 10 mole equivalents,more preferably about 2 to 5 mole equivalents, most preferably about 3mole equivalents, per mole equivalent of the CCA-epoxide.

Preferably, the glycine C₁₋₄ ester is a methyl ester. A preferred saltof the glycine C₁₋₄ ester is glycine hydrochloride. More preferably, theglycine C₁₋₄ ester or salts thereof, is glycin methylesterhydrochloride.

Preferably, the C₁₋₄ ester of 1,3-acetonedicarboxylic acid is selectedfrom the group consisting of symmetrical and mixed C₁₋₄ esterderivatives. The preferred substance comprising a carbonyl moiety is1,3-acetonedicarboxylic acid.

Preferably, the second reaction mixture is maintained at a temperatureof about 0° C. to about 60° C., more preferably, at about 10° C. toabout 40° C., most preferably at about room temperature. The secondmixture is maintained, preferably for about 10 to about 72 hours, andmore preferably for about 12 to about 24 hours, most preferably forabout 18 hours. Maintaining the second reaction mixture is preferablydone while stirring.

The process for preparing the OAN compound of formula V may furthercomprise a recovery step. The recovery may be done by any known process.The OAN compound of formula V may be recovered by filtering off theundissolved solid particles from the second reaction mixture,preferably, through Celite, followed by washing with water, andcombining the filtrate with an inorganic base to obtain a pH of about 7to about 9, more preferably, of about 7.5 to about 8. Preferably, theinorganic base is selected from the group consisting of sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide,potassium carbonate and potassium bicarbonate, more preferably is sodiumbicarbonate. The basic filtrate is then extracted with a waterimmiscible organic solvent, preferably a C₂₋₅ acetate, more preferablyisobutylacetate, and the solvent is evaporated.

The present invention also provides a process for the preparation of aDLS-salt of formula VIIIs comprising preparing the OAN compound offormula V by the process of the invention, and converting it to aDLS-salt of formula VIIIs. This conversion to a DLS salt of formulaVIIIs may be carried out by the process of the invention or any otherknown process converting an OAN compound of formula V to a DLS salt offormula VIIIs as described for example in EP 0339699, examples 4 and 9.

The present invention provides a process for the preparation of anOAN-salt of formula Vs

comprising reacting the OAN compound of formula V, an acid, and anorganic solvent selected from the group consisting of a C₁₋₄ alcohol, aC₂₋₈ ester, a linear, branched or cyclic C₂₋₈ ether, a C₃₋₆ ketone and aC₅₋₈ aliphatic hydrocarbon, a C₁₋₈ halogenated hydrocarbon, a C₁₋₄nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈ aromatic hydrocarbon, a C₃₋₁₀amide and mixtures thereof, wherein, R₁ and R₂ are described before, andZ is an acid, preferably, methanesulfonic acid.

The present invention further provides a process for purifying the OANcompound of formula V comprising reacting the OAN compound of formula V,an acid, and an organic solvent selected from the group consisting of aC₁₋₄ alcohol, a C₂₋₈ ester, a linear, branched or cyclic C₂₋₈ ether, aC₃₋₆ ketone and a C₅₋₈ aliphatic hydrocarbon, a C₁₋₈ halogenatedhydrocarbon, a C₁₋₄nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈ aromatichydrocarbon, a C₃₋₁₀ amide and mixtures thereof; and adding a base.

The OAN compound of formula V used as a starting material may be a crudeOAN compound or a concentrated solution of a crude OAN compound,obtained in the recovery process of the OAN compound.

Preferably, the OAN compound of formula V is dissolved in an organicsolvent selected from the group consisting of a C₁₋₄ alcohol, a C₂₋₈ester, a linear, branched or cyclic C₂₋₈ ether, a C₃₋₆ ketone and a C₅₋₈aliphatic hydrocarbon, a C₁₋₈ halogenated hydrocarbon, a C₁₋₄nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈ aromatic hydrocarbon, a C₃₋₁₀amide and mixtures thereof, prior to adding the acid.

Preferably, the C₁₋₄ alcohol is a C₁₋₃ alcohol. Preferably, the C₁₋₃alcohol is methanol, n-propanol, isopropanol or ethanol. A preferredC₂₋₈ ester is a C₂₋₆ ester, more preferably, a C₂₋₄ ester. A preferredC₂₋₄ ester is ethyl acetate, propylacetate, n-butyl acetate, orisobutylacetate. A preferred linear, branched or cyclic C₂₋₈ ether is aC₂₋₇ ether, more preferably, a C₂₋₅ ether. A preferred C₂₋₅ ether is1,4-dioxane, diisopropyl ether, t-butyl methyl ether or tetrahydrofuran.Preferably, the C₃₋₆ ketone is a C₃₋₅ ketone. Preferably, the C₃₋₅ketone is methyl ethyl ketone (2-butanone), 2-pentanone, 3-pentanone,3,3-dimethyl-2-butanone or acetone. Preferably, the C₅₋₈ aliphatichydrocarbon is a C₅₋₇ aliphatic hydrocarbon, more preferably, a C₆₋₇aliphatic hydrocarbon. A preferred C₆₋₇ aliphatic hydrocarbon is eithern-hexane, or n-heptane. A preferred C₁₋₈ halogenated hydrocarbon is aC₁₋₆ halogenated hydrocarbon, more preferably a C₁₋₄ halogenatedhydrocarbon, most preferably a C₁₋₂ halogenated hydrocarbon. A preferredC₁₋₂ halogenated hydrocarbon is dichloroethane, chloroform ordichloromethane. A preferred C₁₋₄ nitroalkane is a C₁₋₂ nitroalkane.Preferably, the C₁₋₂ nitroalkane is nitromethane or nitroethane.Preferably, the C₁₋₄ alkylcyanide is a C₁₋₃ alkylcyanide. A preferredC₁₋₃ alkylcyanide is either propionitrile or acetonitrile. A preferredC₆₋₈ aromatic hydrocarbon is a C₆₋₇ aromatic hydrocarbon. Preferably,the C₆₋₇ aromatic hydrocarbon is toluene. A preferred C₃₋₁₀ amide is aC₃₋₆ amide. Preferably, the C₃₋₆ amide is dimethylformamide. The morepreferred solvent is a mixture of a C₂₋₄ ester and a C₁₋₃ alcohol, morepreferably, of isobutylacetate and ethanol. Preferably, the mixturecontains isobutylacetate and ethanol in a ratio of about 1:1,respectively.

Preferably, the acid is either an organic acid or an inorganic acid. Theorganic acid is selected from the group consisting of carboxylic acidsand sulfonic acids. Preferably, the carboxylic acid is selected from thegroup consisting of: formic acid, acetic acid, propionic acid,trichloroacetic acetic, trifluoroacetic acid, maleic acid, fumaric acid,succinic acid, oxalic acid, tartaric acid, citric acid, mandelic acid,benzoic acid, salicylic acid, naphthalene carboxylic and dicarboxylicacids. More preferably, the carboxylic acid is tartaric acid. Apreferred sulfonic acid is selected from the group consisting of:methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonicacid, naphthalene sulfonic and disulfonic acids. More preferably, thesulfonic acid is either methane sulfonic acid or camphorsulfonic acid.Preferably, the inorganic acid is selected from the group consisting of:hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, perchloric acid, and fluoroboric acid. The morepreferred inorganic acid is hydrochloric acid. The more preferred acidis methane sulfonic acid.

Combining the OAN compound of formula V, the solvent and the acidprovides a mixture. Preferably, the mixture is maintained at atemperature of about 10° C. to about 60° C., more preferably, at atemperature of about 20° C. to about 50° C., most preferably at atemperature of about 30° C. to about 40° C. The mixture is preferablymaintained at such temperature for about 1 hour to about 24 hours, andmore preferably, for about 2 to about 12 hours. Maintaining the reactionmixture is preferably done while stirring.

Preferably, reacting the OAN compound with an acid provides thecorresponding OAN-salt of formula Vs. Preferably, the OAN-salt offormula Vs precipitates from the reaction mixture. Preferably, in theprocess of purifying the OAN compound of formula V, the precipitate isreacted with a base providing the OAN compound of formula V back again.Preferably, the precipitate is recovered prior to reacting with a base.

Preferably, the base is selected from the group consisting of sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide,potassium carbonate and potassium bicarbonate. More preferably, the baseis sodium bicarbonate.

The process for preparing an OAN-salt of formula Vs may further comprisea process for converting it to a DLS-salt of formula VIIIs.

The present invention provides a process for the preparation of a HANcompound of formula VI

comprising combining an OAN salt of formula Vs, a reducing agent, and asolvent selected from the group consisting of water, water miscibleorganic solvents and mixtures thereof to obtain the HAN compound offormula VI.

Preferably, the OAN-salt of formula Vs is OAN-MsOH. When the OAN-salt isused as a starting material, it is combined with a water miscibleorganic solvent, providing a suspension. Preferably, the suspension isprepared at a temperature of about 15° C. to about 35° C., preferably ofabout 20° C. to about 25° C. Optionally, the OAN compound of formula Vmay be used as a starting material. When, the OAN compound of formula Vis used as a starting material, it is combined with a water miscibleorganic solvent, providing a solution. Preferably, the water miscibleorganic solvent is a C₁₋₄ alcohol, more preferably, a C₁₋₃ alcohol, mostpreferably, a C₁₋₂ alcohol. A preferred C₁₋₂ alcohol is methanol.

Preferably, the reducing reagent is a metal hydride complex, preferablylithium borohydride, selectricde or sodium borohydride, more preferably,sodium borohydride. The reducing agent may be used in a basic aqueoussolution or as a solid. When the OAN compound of formula V is thestarting material, a basic aqueous solution of the reducing agent may beused. Preferably, the basic aqueous solution is an aqueous solution ofan alkali hydroxide, more preferably an aqueous solution of sodiumhydroxide. Preferably, the basic aqueous solution contains about 30% toabout 50% by weight, preferably about 30%, of sodium hydroxide.

Preferably, the solution of the OAN compound of formula V in a C₁₋₄alcohol and the basic aqueous solution of the reducing agent arecombined at a temperature of about 0° C. to about 10° C., preferablyabout 0° C. to about 5° C. Preferably, the solution of the reducingreagent is added drop-wise to the solution of the OAN compound in a C₁₋₄alcohol.

When the OAN-salt of formula Vs is the starting material, a solidreducing agent may be used. Preferably, the suspension of the OAN-saltof formula Vs in a C₁₋₄ alcohol and the reducing agent are combined at atemperature of about 15° C. to about 35° C., preferably about 20° C. toabout 25° C. Preferably, the reducing reagent is added portion-wise tothe suspension of the OAN-salt in a C₁₋₄ alcohol. Preferably, theportion-wise addition of the reducing agent is done while maintainingthe temperature at about 15° C. to about 35° C., preferably about 25° C.to about 35° C.

Combining the above substances leads to a mixture. Preferably, themixture is maintained for about a half hour to about 2 hours, preferablyfor about a half hour to about an hour at such temperature, prior torecovering the HAN compound of formula VI.

When the OAN compound of formula V is used as a starting material, themixture is maintained at a temperature of about 0° C. to about 5° C.,for about an hour, and when the starting material is OAN-salt of formulaVs, the mixture is maintained at a temperature of about 25° C. to about35° C., for about a half an hour. The reaction may be monitored by TLCusing ethylacetate as an eluent.

The process for preparing the HAN compound of formula VI may furthercomprise a recovery step. The recovery may be carried out by any knownmethod. The HAN compound of formula VI may be recovered by a processcomprising adding an acid, preferably a water miscible organic acid,more preferably acetic acid, to the reaction mixture, to give aprecipitate. The precipitate is then combined with water and with ahalogenated hydrocarbon, preferably a C₁₋₂ halogenated hydrocarbon, togive a solution, optionally followed by filtration. The aqueous phase isthen extracted, and the solvent is evaporated form the combined organicphase, providing a crude HAN compound. Optionally, after adding aceticacid, the mixture is evaporated and the residue is combined withethylacetate. The undissolved particles are then, filtered off, and thefiltrate is concentrated, providing a crude HAN compound.

The present invention further provides a process for the preparation ofa HAN-salt of formula VIs,

comprising reacting the HAN compound of formula VI,

an acid, and an organic solvent selected from the group consisting of aC₁₋₄ alcohol, a C₂₋₈ ester, a linear, branched or cyclic C₂₋₈ ether, aC₃₋₆ ketone and a C₅₋₈ aliphatic hydrocarbon, a C₁₋₈ halogenatedhydrocarbon, a C₁₋₄ nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈ aromatichydrocarbon, a C₃₋₁₀ amide, and mixtures thereof, wherein, Z, R₁ and R₂are described before.

When R₁ and R₂ are methyl, said HAN compound of formula VI correspondsto HAN of the following formula,

and when R₁ and R₂ are methyl Z is methane sulfonic acid, said HAN-saltof formula VIs corresponds to HAN-MsOH of the following formula.

The process for preparing the HAN compound of formula VI may furthercomprise a process for converting it to a DLS-salt of formula VIIIs.

The present invention also provides a process for purifying the HANcompound of formula VI comprising combining the HAN compound of formulaVI, an acid, and an organic solvent selected from the group consistingof a C₁₋₄ alcohol, a C₂₋₈ ester, a linear, branched or cyclic C₂₋₈ether, a C₃₋₆ ketone and a C₅₋₈ aliphatic hydrocarbon, a C₁₋₈halogenated hydrocarbon, a C₁₋₄ nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈aromatic hydrocarbon, a C₃₋₁₀ amide, and mixtures thereof; and adding abase.

The HAN compound of formula VI used as a starting material may be acrude HAN compound.

Preferably, the HAN compound of formula VI is dissolved in an organicsolvent selected from the group consisting of a C₁₋₄ alcohol, a C₂₋₈ester, linear, branched or cyclic C₂₋₈ ethers, a C₃₋₆ ketone and a C₅₋₈aliphatic hydrocarbon, a C₁₋₈ halogenated hydrocarbon, a C₁₋₄nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈ aromatic hydrocarbon, a C₃₋₁₀amide, and mixtures thereof, prior to adding the acid.

Preferably, the C₁₋₄ alcohol is a C₁₋₃ alcohol. Preferably, the C₁₋₃alcohol is methanol, ethanol, n-propanol, or isopropanol. A preferredC₂₋₈ ester is a C₂₋₆ ester, more preferably a C₄₋₆ ester. A preferredC₄₋₆ ester is ethyl acetate, propyl acetate, butyl acetate, or isobutylacetate. A preferred linear, branched or cyclic C₂₋₈ ether is a C₂₋₇ether, more preferably a C₂₋₆ ether. A preferred C₂₋₆ ether istetrahydrofuran, 1,4-dioxane, diisopropyl ether, or t-butyl methylether. Preferably, the C₃₋₆ ketone is a C₃₋₅ ketone. Preferably, theC₃₋₅ ketone is acetone, methyl ethyl ketone (2-butanone), 2-pentanone,3-pentanone, or 3,3-dimethyl-2-butanone. Preferably, the C₅₋₈ aliphatichydrocarbon is a C₅₋₇ aliphatic hydrocarbon, more preferably a C₆₋₇aliphatic hydrocarbon. A preferred C₆₋₇ aliphatic hydrocarbon is eithern-hexane, or n-heptane. A preferred C₁₋₈ halogenated hydrocarbon is aC₁₋₆ halogenated hydrocarbon, more preferably a C₁₋₄ halogenatedhydrocarbon, most preferably a C₁₋₂ halogenated hydrocarbon. A preferredC₁₋₂ halogenated hydrocarbon is dichloromethane, dichloroethane, orchloroform. A preferred C₁₋₄ nitroalkane is a C₁₋₂ nitroalkane.Preferably, the C₁₋₂ nitroalkane is nitromethane or nitroethane.Preferably, the C₁₋₄ alkylcyanide is a C₁₋₃ alkylcyanide. A preferredC₁₋₃ alkylcyanide is either acetonitrile or propionitrile. A preferredC₆₋₈ aromatic hydrocarbon is a C₆₋₇ aromatic hydrocarbon. Preferably,the C₆₋₇ aromatic hydrocarbon is toluene. A preferred C₃₋₁₀ amide is aC₃₋₆ amide. Preferably, the C₃₋₆ amide is dimethylformamide. The morepreferred solvent for dissolving the HAN compound of formula VI is aC₂₋₄ ester, most preferably, ethylacetate.

Preferably, the acid is the same as the acid in the process forpreparing the purified OAN compound of formula V. The more preferredacid is methane sulfonic acid.

Combining the HAN compound of formula VI, the solvent and the acidprovides a mixture. Preferably, the mixture is maintained at atemperature of about 10° C. to about 60° C., more preferably, at atemperature of about 20° C. to about 50° C., most preferably at atemperature of about 30° C. to about 40° C. The mixture is preferablymaintained at such temperature for about 0.5 hours to about 24 hours,and more preferably for about 1 hour to about 3 hours, most preferablyfor about 2 hours. Maintaining the reaction mixture is preferably donewhile stirring.

Preferably, reacting the HAN compound with an acid provides acorresponding HAN-salt of formula VIs. Preferably, the HAN-salt offormula VIs precipitates from the reaction mixture. Preferably, in aprocess for purifying the HAN compound of formula VI, the HAN-salt offormula VIs is reacted with a base, providing the HAN compound offormula VI back again. Preferably, the precipitate is recovered prior toreacting with a base.

Preferably, the base is selected from the group consisting of sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide,potassium carbonate and potassium bicarbonate. More preferably, the baseis sodium bicarbonate.

The process for preparing a HAN-salt of formula VIs may further comprisea process for converting it to a DLS-salt of formula VIIIs.

The present invention further provides a process for the preparation ofa7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo[3.3.1]-nonanecompound (referred to as a SAN compound) of formula X

wherein R₁ and R₂ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl,preferably, a C₁₋₄ alkyl, more preferably, methyl, and R₃R₄R₅ areindependently a C₁₋₆ alkyl or a C₆₋₈ aryl, preferably,tert-butyldialkyl, more preferably, tert-butyldimethyl comprisingcombining a HAN compound of formula VI or a salt thereof

a silylating agent selected from the group consisting of: silanes, silylhalogenides, silyl cyanides, silyl amines, silyl amides, silyltrifluoromethanesulfonates (silyl triflates), silazanes, a base, and ana-protic organic solvent forming a mixture to obtain the SAN compound offormula X, wherein, R₁ and R₂ and Z are described before.

When R₁ and R₂ are methyl, and Z is MsOH, said compound of formula VIscorresponds to HAN-MsOH of the following formula,

and said compound of formula X corresponds to SAN of the followingformula.

Preferably, the HAN-salt of formula VI is combined with an a-proticorganic solvent. Preferably, the a-protic organic solvent is selectedfrom a group consisting of a C₁₋₈ halogenated hydrocarbon, a C₂₋₈ ester,a C₂₋₈ ether, C₆₋₈ aromatic hydrocarbon, C₃₋₁₀ amide, and a C₃₋₆ ketoneto obtain a suspension. A preferred C₁₋₈ halogenated hydrocarbon is aC₁₋₅ halogenated hydrocarbon, more preferably, a C₁₋₃ halogenatedhydrocarbon. Preferably, the a C₁₋₃ halogenated hydrocarbon isdichloromethane, 1,2-dichloroethane or chloroform. A preferred C₂₋₈ester is a C₄₋₆ ester. Preferably, the C₄₋₆ ester is ethyl acetate,n-butyl acetate or isobutyl acetate. A preferred C₂₋₈ ether is a C₄₋₆ether. Preferably, the C₄₋₆ ether is diethyl ether, diisopropyl ether ortert-butyl methyl ether. A preferred C₆₋₈ aromatic hydrocarbon is a C₆₋₇aromatic hydrocarbon. Preferably, the C₆₋₇ aromatic hydrocarbon istoluene. A preferred C₃₋₁₀ amide is a C₃₋₆ amide. Preferably, the C₃₋₆amide is dimethylformamide. A preferred C₃₋₆ ketone is a C₄₋₆ ketone.Preferably, the C₄₋₆ ketone is methyl ethyl ketone (2-butanone),2-pentanone, 3-pentanone or 3,3-dimethyl-2-butanone. The preferredsolvent is dichloromethane.

The base is added to the suspension, providing a solution. Preferably,about 2 to about 10 mole equivalent of base per mole equivalent of theHAN-salt is used. More preferably, about 3 to about 6 mole equivalent ofbase per mole equivalent of the HAN-salt is used. Preferably, the baseis selected from the group consisting of: sodium hydroxide, sodiumcarbonate, sodium bicarbonate, potassium hydroxide, potassium carbonatepotassium bicarbonate, trialkyl amines, and N-containing heterocycles.Preferably, the trialkylamine is triethylamine, diisopropylethyl amineor tributyl amine. A preferred N-containing heterocycle is piperidine,pyridine, pyrimidine, piperazine, triazine, pyrrolidine, imidazole, ortriazole. The preferred base is an N-containing heterocycle, morepreferably, imidazole.

Preferably, the base is added at a temperature of about 15° C. to about55° C., more preferably, at 20° C. to about 25° C.

Preferably the silane is selected from the groups consisting oftriethylsilane, triisopropylsilane, and triphenylsilane. Preferably thesilyl halogendie is selected from the group consisting of trimethylsilychloride, tert-butyldimethylsilyl chloride, and tert-butyldiphenylsilylchloride. Preferably the silyl cyanide is selected from the groupconsting of trimethylsilyl cyanide, triethylsilyl cyanide, andtert-butyldimethylsilyl cyanide. Preferably the silyl amine istrimethylsilyldiethylamine or triethylsilyldiethylamine. Preferably thesilyl amide is selected from the group consisting ofN-methyl-N-trimethylsilylacetamide, N-methyl-N-triethylsilylacetamide,and tert-butyldimethylsilyl-N-methyltrifluoroacetamide. Preferably thesilyl triflate is selected from the group consisting of trimethylsilyltrifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, andtert-butyldimethylsilyl trifluoromethanesulfonate. Preferably thesilazane is hexamethyldisilazane or hexaethyldisilazane. Preferably, thesilylating agent is trialkylsilyl halogenide. Preferably, the alkylgroup is t-butyldimethyl. The preferred silylating agent istert-butyldimethylsilyl chloride. Preferably, the silylating agent isadded to the solution, providing a reaction mixture.

Preferably, about 1 to about 4 mole equivalent of silylating agent permole equivalent of the HAN-salt is used. More preferably, about 1.5 toabout 2.5 mole equivalent of sylilating agent per mole equivalent of theHAN-salt is used. Preferably, the mixture is maintained at a temperatureof about 0° C. to about 80° C., more preferably, more preferably at atemperature of about 20° C. to about 60° C., most preferably, at about40° C. to about 60° C. Preferably, the mixture is maintained for about0.5 hours to about 24 hours, and more preferably, for about 4 to about12 hours.

The progress of the reaction may be monitored by HPLC or by TLC. Whenmonitored by TLC, an eluent of ethyl acetate is used.

The process for preparing the SAN compound of formula X may furthercomprise a recovery step. The SAN compound of formula X may be recoveredby extracting the product with water, and evaporating the solvent.

The SAN compound of formula X may also be prepared from the HAN compoundof formula VI

using similar conditions as used when the HAN-salt of formula VIs is thestarting material, however, a smaller amount of base and of a silylatedagent may be used and the most preferred solvent is dichloromethane.Preferably, when the HAN compound of formula VI is the startingmaterial, about 1 to about 5 mole equivalent of base per mole equivalentof the HAN compound is used, more preferably, about 1 to about 3 moleequivalent of base per mole equivalent of the HAN compound is used.Preferably, about 1 to about 3 mole equivalent of silylating agent permole equivalent of the HAN compound is used. More preferably, about 1 toabout 2 mole equivalent of silylating agent per mole equivalent of theHAN compound is used.

The process for preparing the SAN compound of formula X may furthercomprise a process for converting it to a DLS-salt of formula VIIIs.

The present invention provides a process for the preparation of a SQOcompound of formula XII

comprising mixing a SAN compound of formula X, a metal alkoxide, and apolar a-protic organic solvent to form a mixture; heating the mixture;and reacting this mixture with a weak acid, forming the SQO compound offormula XII, wherein, R, R₃R₄ and R₅ are described before.

When R is methyl, and R₃R₄R₅ are tert-butyldimethyl said compound offormula XII corresponds to SQO of the following formula.

A preferred polar a-protic organic solvent is selected from the groupconsisting of a C₂₋₈ ether having a boiling point of about 60° C. toabout 100° C. Preferably, the C₂₋₈ ether having a boiling point of about60° C. to about 100° C. is tetrahydrofuran (referred to as THF),2-methyltetrahydrofuran, tetrahydropyran, monoglyme, diisopropyl ether,or methyl t-butyl ether. The more preferred polar aprotic organicsolvent is THF.

Preferably, the SAN compound of formula X is dissolved in a polara-protic organic solvent, prior to adding the metal alkoxide.

Preferably, the metal alkoxide is selected from the group consisting oflithium alcoholates, sodium alcoholates and potassium alcoholates;wherein the alcoholate moiety contains 1 to 4 carbons. More preferably,the metal alkoxide is potassium tert-butoxide.

Combining the SAN compound of formula X, the polar a-protic organicsolvent and the metal alkoxide provides a solution. Preferably, thesolution is heated to a temperature of about 40° C. to about 120° C.,more preferably, to a temperature of about 60° C. to about 80° C. Thesolution is heated, preferably, for about 0.5 hours to about 8 hours,and more preferably, for about 1 hour to about 3 hours. Heating thesolution is preferably done under stirring.

While heating, the solution is concentrated, preferably, by distillationof the polar a-protic organic solvent, providing a mixture. The mixtureis, preferably, cooled to a temperature of about 0° C. to about 30° C.,more preferably, to a temperature of about 15° C. to about 25° C., priorto reacting with the acid.

Preferably, the weak acid is selected from the group consisting ofacetic acid, formic acid, propionic acid, maleic acid, fumaric acid,succinic acid, oxalic acid, tartaric acid, citric acid, mandelic acid,benzoic acid, salicylic acid, naphthalene carboxylic and dicarboxylicacids, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, benzenesulfonic acid, naphthalene sulfonic and disulfonic acids.Preferably, the acid is a water miscible organic acid, preferably aceticacid, more preferably acetic acid combined with water, providing adiluted aqueous solution of acetic acid. Preferably, the acid is addedto the cooled mixture, providing an acidic mixture, prior to recoveringthe SQO compound of formula XII. Preferably, the pH of the acidicmixture is of about 4 to about 6, more preferably, of about 5 to about6.

The process for preparing the SQO compound of formula XII may furthercomprise a step of recovering it. The recovery may be carried out by anyknown method. The SQO compound of formula XII may be recovered by aprocess comprising combining the acidic mixture with a base, providing aslight basic mixture; concentrating the slight basic mixture;precipitating the SQO compound of formula XII; and recovering it.

Preferably, the pH of the slightly basic mixture is of about 7 to about8. Preferably, the base is selected from a group consisting of sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide,potassium carbonate and potassium bicarbonate. The more preferred baseis sodium bicarbonate.

Preferably, the basic mixture is concentrated by removing the polara-protic organic solvent. Preferably, removal of the polar a-proticorganic solvent is done by distillation. The removal of the polara-protic organic solvent provides a concentrated aqueous mixture.Preferably, the precipitation of the SQO compound of formula XII is doneby cooling the concentrated aqueous mixture to about 0° C. to about 10°C., preferably about 2° C. to about 8° C. The cooled concentratedaqueous mixture is maintained, preferably, for about 3 hours to about 24hours, and more preferably, for about 8 hours to about 18 hours, priorto filtering the precipitate. The filtered SQO compound of formula XIIis washed with water, and dried.

The process for preparing the SQO compound of formula XII may furthercomprise a process for converting it to a DLS-salt of formula VIIIs.

The present invention also provides a process for preparing HQO offormula II

comprising mixing a SQO compound of formula XII, a solvent selected fromthe group consisting of water and a water-miscible organic solvent, andan acid to obtain HQO.

Preferably, the acid is selected from the group consisting ofhydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, perchloric acid, fluoroboric acid, methanesulfonicacid, ethanesulfonic acid, trifluoromethanesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid,naphthalene sulfonic and disulfonic acids.

Preferably, the SQO compound of formula XII is combined with water or awater-miscible organic solvent to obtain a suspension. Preferably, thewater-miscible organic solvent is dimethylformamide, dimethylacetamide,dimethyl sulfoxide, or diglyme, more preferably dimethylformamide.Preferably, the SQO compound of formula XII is combined with water at atemperature of about 10° C. to about 50° C., more preferably, at 20° C.to about 25° C.

Preferably, the acid is added to the suspension providing a solution.Preferably, the addition of the acid provides an acidic solution.Preferably, the acidic solution has a pH of about 0.5 to about 3, morepreferably, of about 1 to about 2.

The acidic solution is heated, preferably, to a temperature of about 80°C. to about 100° C. The heated solution is maintained, preferably, forabout 3 hours to about 24 hours, and more preferably, for about 6 hoursto about 10 hours. Heating the solution is preferably done whilestirring.

The progress of the reaction may be monitored by HPLC or by TLC. Whenmonitored by TLC, an eluent of methylene chloride and methanol in aratio of 1:1 is used.

The process for preparing HQO of formula II may further comprise arecovery step. The recovery may be carried out by any known method. HQOof formula II may be recovered by cooling the heated acidic solution,adding a base to the cooled acidic mixture, extracting the product witha water immiscible organic solvent, and evaporating the water immiscibleorganic solvent to obtain HQO of formula II.

Preferably, the heated solution is cooled to a temperature of about 0°C. to about 30° C., more preferably, to a temperature of about 15° C. toabout 25° C.

Preferably, a base is added to the cooled solution. Preferably, the baseis selected from the group consisting of sodium hydroxide, sodiumcarbonate, sodium bicarbonate, potassium hydroxide, potassium carbonateand potassium bicarbonate. The more preferred base is sodium hydroxide.Preferably, the addition of the base provides a basic mixture.Preferably, the basic mixture has a pH of about 8 to about 13, morepreferably, of about 11 to about 12.

The preferred water immiscible organic solvent is selected from thegroup consisting of a C₂₋₈ ester, a linear, branched or cyclic C₂₋₈ether, a C₃₋₆ ketone and a C₅₋₈ aliphatic hydrocarbon, and a C₁₋₈halogenated hydrocarbon. The most preferred water immiscible organicsolvent is methylene chloride. A preferred C₂₋₈ ester is a C₄₋₆ ester.Preferably, the C₄₋₆ ester is ethyl acetate, n-butyl acetate or isobutylacetate. A preferred C₂₋₈ ether is a C₄₋₆ ether. Preferably, the C₄₋₆ether is diethyl ether, diisopropyl ether or tert-butyl methyl ether. Apreferred C₃₋₆ ketone is a C₄₋₆ ketone. Preferably, the C₄₋₆ ketone ismethyl ethyl ketone (2-butanone), 2-pentanone, 3-pentanone or3,3-dimethyl-2-butanone. A preferred C₅₋₈ aliphatic hydrocarbon is aC₆₋₇ aliphatic hydrocarbon. Preferably, the C₆₋₇ aliphatic hydrocarbonis n-hexane or n-heptane. A preferred C₁₋₈ halogenated hydrocarbon is aC₁₋₂ halogenated hydrocarbon. Preferably, the C₁₋₂ halogenatedhydrocarbon is dichloromethane, 1,2-dichloroethane or chloroform.

Optionally, HQO of formula II may be prepared directly from the SANcompound of formula X, i.e., without isolating the SQO compound offormula XII. Preferably, the reaction may include the same steps asdescribed in the process for preparing the SQO compound of formula XII,but using a strong acid instead of a weak acid, and heating. Preferably,the stron acid is selected from the group consisting of methanesulfonicacid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromicacid, and triflic acid.

This process for preparing HQO of formula II from the SQO compound offormula XII or directly from the SAN compound of formula X may furthercomprise a process for converting it to a DLS-salt of formula VIIIs.

Preferably, reacting SAN with an acid provides the corresponding salt ofHQO, a HQO-salt of formula IIs. Preferably, the HQO-salt of formula IIsprecipitates in the reaction mixture. Preferably, the HQO-salt offormula IIs is reacted with a base, providing HQO of formula II backagain. Preferably, the precipitate is recovered prior to reacting with abase.

Preferably, the base is selected from the group consisting of sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide,potassium carbonate, and potassium bicarbonate, more preferably sodiumbicarbonate.

The present invention also provides another process for the preparationof a HQO-salt of formula IIs comprising combining HQO, an alcohol and anacid selected from the group consisting of: hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,perchloric acid, fluoroboric acid, formic acid, acetic acid, propionicacid, trichloroacetic acid, trifluoroacetic acid, maleic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, citric acid, mandelicacid, benzoic acid, salicylic acid, naphthalene carboxylic anddicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonicacid, naphthalene sulfonic, and disulfonic acid to obtain a HQO salt offormula IIs.

The present invention provides a process for purifying HQO of formula IIby a process comprising combining HQO of formula II, an alcohol and anacid selected from the group consisting of: hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,perchloric acid, fluoroboric acid, formic acid, acetic acid, propionicacid, trichloroacetic acid, trifluoroacetic acid, maleic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, citric acid, mandelicacid, benzoic acid, salicylic acid, naphthalene carboxylic anddicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonicacid, naphthalene sulfonic, and disulfonic acid forming a mixture, andadding a base to obtain purified HQO.

Preferably, the alcohol is a C₁₋₄ alcohol, more preferably, ethanol.

Preferably, the acid is an organic acid, more preferably, a sulfonicacid, most preferably, methanesulfonic acid.

The process for preparing a HQO-salt of formula IIs can further comprisea process for converting it to a DLS-salt of formula VIIIs.

HQO-salt of formula IIs may be converted to a DLS-salt of formula VIIIscomprising converting it to the free base, HQO of formula II; reactingHQO with a base to form a reaction mixture; mixing the reaction mixturewith an anhydride, indole-3-carboxylic acid, an organic solvent, and acatalyst to form a mixture; and reacting the mixture with an acid, toobtain the DLS-salt of formula VIIIs.

Preferably, the base is selected from the group consisting of sodiumhydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide,potassium carbonate and potassium bicarbonate. The more preferred baseis sodium bicarbonate.

Preferably, the organic solvent is selected from the group consisting ofa C₁₋₂ halogenated hydrocarbon, a C₆₋₈ aromatic hydrocarbon, a C₁₋₄nitroalkane, a C₁₋₄ alkyl cyanide, trifluoroacetic acid and mixturesthereof. A preferred C₁₋₂ halogenated hydrocarbon is dichloromethane,1,2-dichloroethane or chloroform, more preferably dichloromethane. Apreferred C₆₋₈ aromatic hydrocarbon is benzene, toluene or xylol, morepreferably toluene. Preferably, the C₁₋₄ nitroalkane is a C₁₋₂nitroalkane, either nitromethane or nitroethane, more preferablynitromethane. Preferably, the C₁₋₄ alkyl cyanide is a C₁₋₂ alkylcyanide, either acetonitrile or propionitrile, more preferablyacetonitrile.

Preferably, the anhydride is either trifluoroaceticanhydride or methylchlorocarbonate, more preferably, trifluoroaceticanhydride.

Preferably, indole-3-carboxylic acid is added drop-wise, morepreferably, over a period of about 10 minutes to about 30 minutes,preferably about 15 minutes.

Preferably, the catalyst is either a saturated trisubstituted amine oran aromatic amine. Preferably, the saturated trisubstituted amine iseither a trialkyl amine or 4-dialkylaminopyridine amine. Preferably, thetrisubstituted amine is 4-dimethylaminopyridine ordiisopropylethylamine, more preferably, 4-dimethylaminopyridine.

Preferably, HQO and the catalyst are added at the same time to asolution of the anhydride, the organic solvent and the3-indole-carboxylic acid, providing a reaction mixture. Preferably, thereaction mixture is heated to a temperature of about 25° C. to about 40°C., more preferably to about 30° C. to about 35° C., for about 2 toabout 18 hours, more preferably for about 2 hours, and preferably whilestirring, providing Dolasetron base.

Dolasetron base may be recovered by removing the solvent to obtain aprecipitate and filtering off the precipitate.

Dolasetron may be converted to Dolasetron salt by combining Dolasetronwith an acid. Preferably, Dolasetron may be converted to Dolasetronmesylate monohydrate by combining Dolasetron, a mixture of acetone andwater, and methane sulfonic acid.

Combining Dolasetron and the mixture of acetone and water provides asuspension, in which the solid dissolves when adding methane sulfonicacid. After complete dissolution, a precipitate of DLS-MsOH is obtained.The precipitate may be maintained in a fridge, and recovered byfiltration, washing and drying.

Having thus described the invention with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the invention as described and illustratedthat do not depart from the spirit and scope of the invention asdisclosed in the specification. The Examples are set forth to aid inunderstanding the invention but are not intended to, and should not beconstrued to limit its scope in any way.

EXAMPLES Example 1 Preparation of CCA-Epoxide of Formula IV

CCA-Me ester (37.8 g, 0.3 mol) was dissolved in 60 ml of methanolfollowed by the addition of hydrogen peroxide (30-35%, 43 ml, 1.3equiv.) and sodium tungstate dihydrate (2 g, 2 mol %). The yellowreaction mixture was refluxed slightly (at 60-65° C.) for 2-4 hoursuntil the reaction was completed (GC or TLC: eluent n-hexane-ethylacetate 1:1, visualized by iodine). After cooling it was extracted withmethylene chloride (3×100 ml). The combined organic phases were dried onsodium sulfate and evaporated to dryness. The product was 40.5 gcolorless oil (95% yield).

Example 2 Preparation of OAN of Formula V

To a well-stirred solution of periodic acid (32 g, 0.14 mol) in water(200 ml) was added CCA-epoxide (19 g, 0.14 mol), and the reactionmixture was stirred at 10-15° C. for 1 hour. After completion, thereaction mixture having a pH of 1, was cooled and the pH was adjusted to3.5-4 by the addition of OH-resin (or poly(4-vinylpyridine)), followedby stirring the mixture for 10-15 min at room temperature. The solidmaterial was filtered through a layer of Celite and washed with water(2×150 ml). To the aqueous solution were added sequentially at roomtemperature (86 g, 0.42 mol, 3 equiv) potassium hydrogen phthalate, (21g, 0.17 mol, 1.2 equiv) glycine methyl ester hydrochloride and (25 g,0.17 mol, 1.2 equiv) 1,3-acetonedicarboxylic acid. The dark red reactionmixture was stirred at room temperature for 18 h (overnight). Theundissolved solid was filtered through a layer of Celite, washed with asmall volume of water (2×50 ml). To the solution was added, in portions,solid sodium hydrogen carbonate (until pH 7.5-8), then the solution wasextracted with isobutyl acetate (5×200 ml). The combined organic phaseswere dried on sodium sulfate and evaporated to dryness or to a reducedvolume of about 40 ml.

TLC: n-hexane-ethyl acetate 1:1, visualized by UV-light and/or iodine.

Example 3 Preparation of OAN-MsOH Salt of Formula Vs

Crude OAN (600 g) was dissolved in isopropanol (3 L) at room temperaturefollowed by the addition of (144 ml, 1 equiv) methanesulfonic acid,under stirring. The mixture was warmed to 30-40° C., and stirred forovernight. The precipitated oil solidified. The salt was filtered atroom temperature, washed with isopropanol (600+2×300 ml) and dried.

The overall yield (from CCA-epoxyide): 35-40% (purity: <90%).

Example 4 Preparation of OAN-MsOH Salt of Formula Vs

OAN solution in isobutyl acetate (1.2 L, containing 600 g of OAN) wascombined with ethanol (1.2 L) at room temperature followed by theaddition of (144 ml, 1 equiv) methanesulfonic acid, under stirring. Themixture was stirred for 3 hours. The salt was filtered, washed with amixture of isobutyl acetate-ethanol 1:1 ( 12×300 ml) and dried.

The overall yield (from CCA-epoxyide): 35-40%.

Example 5 Preparation of HAN of Formula VI

Sodium borohydride (71 g, 1.4 equiv.) was dissolved in a mixture ofwater (500 ml) and aqueous solution of sodium hydroxide (30%, 14 ml).OAN (361 g, 1.34 mol) was dissolved in methanol (3.6 L), and thesolution was cooled to 0-5° C. The solution of sodium borohydride wasadded drop-wise to the solution of OAN in methanol, and the mixture wasstirred at 0-5° C. for about 1 hour. The reaction was monitored by TLC(eluent:ethyl acetate). After completion of reaction acetic acid (80 ml)was added under stirring while cooling (foaming, warning andprecipitating). Water (0.5 L) and methylene chloride (1 L) were added(filtration can be necessary). The aqueous phase was extracted with (2×1L) of methylene chloride. The combined organic phases were dried onsodium sulfate and evaporated to dryness. The yield was 70%.

Example 6 Preparation of HAN of Formula VI

(14.6 g, 40 mmol) OAN-MsOH was suspended at 20-25° C. in (300 ml)ethanol, then to this suspension (4.2 g, 2.8 equiv) sodium borohydridewas added in portions in order to keep the inner temperature between25-35° C. After addition of the reducing agent the reaction mixture wasstirred for additional 30 minutes. The conversion was monitored by TLC(eluent:ethyl acetate), when it was complete (4.5 ml) acetic acid wasadded (pH 6-7) and the mixture was evaporated to dryness on rotavapor at35-40° C. The residue was mixed with ethyl acetate (60 ml), the unsolvedmaterial was filtered off and the filtered material was washed withethyl acetate (2×20 ml). The filtrate was concentrated on rotavapor at35-40° C., to obtain 10.2 g (94%) of crude HAN.

Example 7 Preparation of HAN-MsOH Salt of Formula VIs

Crude HAN (17 g) was dissolved in ethyl acetate (100 ml) at roomtemperature and (3.6 ml, 1.1 equiv) of methanesulfonic acid was addedunder stirring. The mixture was heated to 30-40° C., and was stirred for2 hours. The precipitated oil solidified. The salt was filtered at roomtemperature, washed with ethyl acetate (2×30 ml) and dried. Yield was80%.

Example 8 Preparation of HQO—CSA Salt of Formula IIs

To a solution of HQO (0.18 g, 1 mmol) in (3 ml) ethanol was addedcamphorsulfonic acid (0.23 g) in (2.5 ml) ethanol. The mixture wasstirred for 20 minutes, filtered, then the solid material was washedwith ethyl acetate and dried.

Example 9 Example 13: Preparation of DLS-Base with Catalyst

To a solution of 52.9 ml (1.3 equiv) trifluoroacetic anhydride in 1.0 Lof dry dichloromethane 47.5 g (1.3 equiv) indole-3-carboxylic acid wasadded in portions within 15 minutes. The reaction mixture was cooled to20-25° C. and after 5 minutes 48.5 g (0.27 mol) HQO and 0.33 g (1 mol %)4-dimethylaminopyridine were added in one portion. The reaction mixturewas heated to 30-35° C. and stirred for 2 hours, then 26.5 ml (0.7equiv) trifluoroacetic anhydride was added. The reaction mixture wasstirred for additional 2 hours, then diluted with 800 ml of 10% sodiumcarbonate. From the mixture dichloromethane was distilled off. Theprecipitated solid was filtered, washed with water (3×100 ml) and dried.Yield is 97%.

Crude Dolasetron base (84 g) was dissolved in isobutyl acetate (2.6 L)at 95-100° C. Charcoal (4.2 g) was added to the solution, and after 10minutes of stirring it was filtered off, and washed with isobutylacetate (0.26 L). The solution was evaporated under reduced pressure toobtain a residue weighing 0.5-0.6 kg, which allowed to cool to roomtemperature, and then further cooled in a fridge overnight. Theprecipitated crystals were filtered off, washed with isobutyl acetate(2×50 ml), and dried overnight at 40-45° C. under reduced pressure.Yield was 88%.

Example 10 Preparation of DLS-Base Without Catalyst

Indole-3-carboxylic acid (17.7 g, 1.1 equiv.) was added in portions to asolution of trifluoroacetic anhydride (20 ml, 1.4 equiv.) in a mixturetoluene (360 ml) and trifluoroacetic acid (90 ml), at room temperature(20-25° C.), during 15 minutes. After 5-minutes of stirring,endo-5-hydroxy-8-azatricyclo[5.3.1.0^(3,8)]-undecan-10-one (18.12 g, 0.1mol), was added in one portion. The reaction mixture heated to 30-35°C., the solid phase dissolved. The solution was stirred for 2 hourswithout external heating. The trifluoroacetic acid was removed byevaporation under reduced pressure until starting of crystallization.10% of an aqueous solution of sodium carbonate (360 ml) was added, thentoluene was removed by evaporation under reduced pressure. Theprecipitated Dolasetron base monohydrate was collected by filtration,washed with water (3×60 ml), and dried overnight at 40° C. under reducedpressure. The dry product was weighed as 33.63 g (98%).

The dried crude Dolasetron base was dissolved in isobutyl acetate (1 L)at 95-100° C. Charcoal (1.7 g) was added to the solution, and after 10minutes of stirring it was filtered off, and washed with isobutylacetate (0.1 L). The solution was evaporated under reduced pressure toobtain a residue weighing 0.20-0.25 kg, which allowed to cool to roomtemperature, and then further cooled in a fridge overnight. Theprecipitated crystals were filtered off, washed with isobutyl acetate(2×20 ml), and dried overnight at 40-45° C. under reduced pressure.Yield was 88%.

Example 11 Preparation of DLS-MsOH of Formula VIII

Methanesulfonic acid (2.85 ml, 1 equiv) was added to a stirredsuspension of Dolasetron base (14.24 g, 43.9 mmol) in a mixture ofacetone-water 95:5 (100 ml). The solid dissolved immediately, after someminutes the salt precipitated in crystalline form. The mixture was putinto fridge, after 4 hours the salt was filtered off, washed with samesolvent mixture (2×15 ml), dried overnight in an air-ventilated oven at40° C. The yield was 15.63 g (81%).

Example 12 Preparation of SAN from HAN

In a 250-ml flask HAN (41 mmol) was dissolved in methylene chloride (120ml). The solution was mixed with 1.5 equiv (7 g) of imidazole at 20-25°C. After complete dissolution, to this solution 1.3 equiv (12.4 g) oftert-butyldimethylsilyl chloride was added and the reaction mixture wasstirred for 6 hours. The conversion was monitored by TLC (eluent:ethylacetate). The reaction mixture was washed with water (2×40 ml). Thecombined aqueous layer was washed with methylene chloride (120 ml). Thecombined organic phase was dried on sodium sulfate, evaporated todryness on rotavapor at 40-45° C. The product was about 19 g of oil.

Example 13 Preparation of SAN from HAN-Mesylate

In a 500-ml flask HAN-mesylate (70 mmol) was mixed with methylenechloride (260 ml). To the suspension 4.5 equiv (21 g) of imidazole wasadded at 20-25° C. After complete dissolution, to this solution 2 equiv(21 g) of tert-butyldimethylsilyl chloride was added and the reactionmixture was stirred for 2 days at 40-45° C. The conversion was monitoredby TLC (eluent:ethyl acetate). The reaction mixture was diluted withmethylene chloride (260 ml), washed with water (2×130 ml). The combinedorganic phase was dried on sodium sulfate, evaporated to dryness onrotavapor at 40-45° C. The product is about 32 g of oil.

Example 14 Preparation of SQO

In a 250-ml flask the crude SAN (ca 19 g, theoretically 41 mmol) wasdissolved in THF (190 ml) and potassium tert-butoxide (9.2 g, 2 equiv)was added under stirring. The solution was heated to reflux for 2 hours,and 95 ml of THF was distilled off during this reflux period. Themixture was cooled to 20-25° C. and aqueous acetic acid (5.4 ml/94mmol/of acetic acid in 80 ml of water) was added, then the pH isadjusted to 7-8 by addition of solid sodium hydrogencarbonate (6-7 g).The rest of THF was distilled off, then the aqueous mixture was cooledto 20-25° C., and stored in the fridge (2-8° C.) overnight. Theprecipitated material was filtered off, washed with water, and dried invacuum. The product was 7.5 g of white solid.

Example 15 Preparation of HQO from SQO

In a 250-ml flask SQO (10.6 g) was suspended in 22 ml of water at 20-25°C. and 3 equiv (4.5 ml) cc HCl was added. The obtained clear solution(pH 1) was stirred for 6 hours at reflux temperature. The conversion wasmonitored by TLC (eluent: 1:1 methylene chloride-methanol). The reactionmixture was cooled to 20-25° C. and the pH of the solution was adjustedto 12 by addition of solid sodium hydroxide under cooling. The solutionwas extracted with methylene chloride (5×50 ml). The combined organicphase was dried on sodium sulfate, and evaporated to dryness onrotavapor at 30-35° C. The residue was 4.7 g of white solid.

Example 16 Preparation of HQO from SAN

In a 250-ml flask the crude SAN (ca 4 g, theoretically 10 mmol) wasdissolved in THF (50 ml) and potassium tert-butoxide (1.6 g, 1.4 equiv)was added under stirring. The solution was heated to reflux for 2 hours,and 25 ml of THF was distilled off during this reflux period. Themixture was cooled to 20-25° C., diluted with water (15 ml), and the pHwas adjusted to 1 with concentrated HCl. The rest of THF was distilledout, and the mixture was refluxed for 6 hours, then cooled to 20-25° C.The pH of the solution was adjusted to 12 by addition of solid sodiumhydroxide under cooling. The basic solution was extracted with methylenechloride (5×30 ml). The combined organic phase was dried on sodiumsulfate, and evaporated to dryness. The residue was 0.82 g of brownishsolid.

1. A quaternary ammonium salt of a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-onecompound (an OAN salt) of formula Vs,

wherein R₁ and R₂ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl, and Zis an acid.
 2. (canceled)
 3. The quaternary ammonium salt of claim 1,wherein R₁ and R₂ are methyl and Z is methanesulfonic acid.
 4. Thequaternary ammonium salt of claim 3, wherein the quaternary ammoniumsalt is crystalline.
 5. The quaternary ammonium salt of claim 4, whereinthe quaternary ammonium salt is crystalline OAN-MsOH is characterized bya powder XRD diffraction pattern having peaks at about 8.5, 18.0, and20.9 degrees two-theta, ±0.2 degrees two-theta.
 6. (canceled)
 7. Thequaternary ammonium salt of claim 6, wherein the crystalline OAN-MsOH ischaracterized having a PXRD pattern as depicted in FIG.
 1. 8. Aquaternary ammonium salt of7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-ol(a HAN salt) of formula VIs,

wherein R₁ and R₂ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl, and Zis an acid.
 9. (canceled)
 10. The quaternary ammonium salt of claim 8,wherein R₁ and R₂ are methyl and Z is methanesulfonic acid.
 11. Thequaternary ammonium salt of claim 10, wherein the quaternary ammoniumsalt is crystalline.
 12. The quaternary ammonium salt of claim 11,wherein the quaternary ammonium salt is crystalline HAN-MsOHcharacterized by a powder XRD diffraction pattern having peaks at about7.3, 11.6, and 14.6 degrees two-theta, ±0.2 degrees two-theta. 13.(canceled)
 14. (canceled)
 15. A7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo[3.3.1]nonanecompound (a SAN compound) of formula X

wherein R₁ and R₂ are independently C₁₋₆ alkyl or C₆₋₈ aryl, and R₃R₄R₅are independently a C₁₋₆ alkyl or a C₆₋₈ aryl, or R₃R₄R₅ together are atert-butyldialkyl.
 16. (canceled)
 17. The compound of claim 15, whereinR₁ and R₂ are methyl and R₃R₄R₅ is tert-butyldimethyl.
 18. Anendo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-onecompound (a SQO compound) of formula XII

wherein R is a C₁₋₆ alkyl or a C₆₋₈ aryl, and R₃R₄R₅ are independently aC₁₋₆ alkyl or a C₆₋₈ aryl, or R₃R₄R₅ together are a tert-butyldialkyl.19. (canceled)
 20. The compound of claim 18, wherein R is methyl, andR₃R₄R₅ are together tert-butyldimethyl.
 21. The compound of claim 20,wherein the compound is crystalline.
 22. The compound of claim 21,wherein the compound is crystalline SQO, characterized by a powder XRDdiffraction pattern having peaks at about 5.1, 10.1, 12.7, and 20.3degrees two-theta, ±0.2 degrees two-theta.
 23. (canceled)
 24. (canceled)25. A quaternary ammonium salt ofendo-5-hydroxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-one (a HQO salt)of formula IIs,

wherein Y an acid selected from the group consisting of: hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,perchloric acid, fluoroboric acid, formic acid, acetic acid, propionicacid, trichloroacetic acid, trifluoroacetic acid, maleic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, citric acid, mandelicacid, benzoic acid, salicylic acid, naphthalene carboxylic anddicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonicacid, naphthalene sulfonic and disulfonic acid.
 26. The quaternaryammonium salt of claim 25, wherein Y is Hydrochloric acid (HQO-HCl). 27.The quaternary ammonium salt of claim 26, wherein the salt iscrystalline.
 28. (canceled)
 29. The quaternary ammonium salt of claim25, wherein Y is Camphorsulfonic acid (HQO—CSA).
 30. The quaternaryammonium salt of claim 29, wherein the salt is crystalline. 31.(canceled)
 32. A method for the preparation of a CCA-epoxide of formulaIV

comprising combining a CCA-ester of formula III,

an oxidizing agent, a catalyst, and a solvent selected from the groupconsisting of water, a water miscible organic solvent, and mixturesthereof forming a mixture, to obtain the CCA-epoxide of formula IV,wherein, R₁ is a C₁₋₆ alkyl or C₆₋₈ aryl.
 33. The method of claim 32,wherein RI is methyl.
 34. The method of claim 32, wherein the oxidizingagent is selected from the group consisting of: hydroxyperoxide, dialkylperoxide, peroxyacid, peroxyester, diacyl peroxide, persulphate,perborate, and perphosphate.
 35. (canceled)
 36. The method of claim 34,wherein the hydroperoxide is hydrogen peroxide.
 37. The method of claim32, wherein the water miscible organic solvent is selected from thegroup consisting of linear or branched C₁₋₄ alcohols.
 38. (canceled) 39.The method of claim 32, wherein the solvent is a mixture of water and awater immiscible organic solvent in the presence of a phase transfercatalyst.
 40. The method of claim 39, wherein the water immiscibleorganic solvent is selected from the group consisting of a C₁₋₈halogenated hydrocarbon, a C₂₋₈ ester, a C₂₋₈ ether and a C₃₋₆ ketone.41. The method of claim 32, wherein the catalyst is selected from thegroup consisting of Zeolites and polyoxometalates.
 42. The method ofclaim 41, wherein the metal moiety of the polyoxometalates is selectedfrom the group consisting of tungsten, molybdenum, rhenium, vanadium andniobium.
 43. (canceled)
 44. (canceled)
 45. The method of claim 32,wherein the reaction mixture is maintained at a temperature of about 0°C. to about 80° C.
 46. The method of claim 32, further comprisingrecovering the CCA-epoxide of formula IV.
 47. (canceled)
 48. (canceled)49. (canceled)
 50. A method for the preparation of a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-onecompound (an OAN compound) of formula V

comprising a) combining a CCA-epoxide of formula IV, an oxidizing agent,and a solvent selected from the group consisting of water, watermiscible organic solvent, and mixtures thereof to form a reactionmixture; b) raising the pH of the reaction mixture; and c) reacting thereaction mixture of step b) with a pH 4 buffer, a glycine C₁₋₄ ester orsalts thereof, and a substance containing a carbonyl moiety selectedfrom the group consisting of 1,3-acetonedicarboxylic acids, acetone andC₁₋₄ esters thereof to form an OAN compound of formula V, wherein R₁ andR₂ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl.
 51. The method ofclaim 50, wherein R₁ and R₂ are methyl.
 52. The method of claim 50,wherein the water miscible organic solvent is selected from the groupconsisting of: a C₂₋₄ nitrile, a C₃₋₆ ketone and a cyclic ether. 53.(canceled)
 54. The method of claim 50, wherein the solvent is water. 55.The method of claim 50, wherein the oxidizing agent is selected from thegroup consisting of: periodic acid and salts thereof, lead tetraacetate,cerium and ammonium nitrate (Ce(NH₄)₂(NO₃)₆).
 56. (canceled)
 57. Themethod of claim 50, wherein the reaction mixture is maintained at atemperature of about 10° C. to about 60° C.
 58. The method of claim 57,wherein the pH of the first reaction mixture is of about 0.5 to about 7.59. (canceled)
 60. The method of claim 59, wherein the pH is raised byusing a water immiscible base selected from poly(4-vinylpyridine) and OHresins.
 61. The method of claim 50, wherein the pH 4 buffer is anamine-free buffer selected from the group consisting of: citricacid-sodium hydroxide-hydrochloric acid, citric acid-disodiumhydrogenphosphate, sodium acetate-acetic acid, potassiumdiphthalate-sodium hydroxide, sodium dihydrogen phosphate and potassiumhydrogen phthalate.
 62. (canceled)
 63. (canceled)
 64. (canceled) 65.(canceled)
 66. The method of claim 64, wherein the glycine C₁₋₄ ester isglycin methylester hydrochloride.
 67. The method of claim 50, whereinthe substance comprising a carbonyl moiety is 1,3-acetonedicarboxylicacid.
 68. The method of claim 50, wherein the reaction mixture in stepc) is maintained at a temperature of about 0° C to about 60° C. 69.(canceled)
 70. (canceled)
 71. The method of claim 50, furthercomprising; combining the OAN compound of formula V, an acid, and anorganic solvent selected from the group consisting of a C₁₋₄ alcohol, aC₂₋₈ ester, a linear, branched or cyclic C₂₋₈ ether, a C₃₋₆ ketone, aC₅₋₈ aliphatic hydrocarbon, a C₁₋₈ halogenated hydrocarbon, a C₁₋₄nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈ aromatic hydrocarbon, a C₃₋₁₀amide, and mixtures thereof, forming a mixture to obtain an OAN-salt offormula Vs

wherein, R₁ and R₂ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl, and Zis an acid.
 72. The method of claim 71, wherein Z is methanesulfonicacid.
 73. (canceled)
 74. (canceled)
 75. (canceled)
 76. The method ofclaim 71, wherein the mixture of the OAN compound of formula V, thesolvent and the acid form is maintained at a temperature of about 10° C.to about 60° C.
 77. The method of claim 71, further comprising adding abase, wherein the OAN compound of formula V is obtained as a purifiedcompound.
 78. (canceled)
 79. (canceled)
 80. A method of preparing a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-9-azabicyclo[3.3.1]nonane-3-olcompound (a HAN compound) of formula VI

comprising combining an OAN salt of formula Vs, a reducing agent, and asolvent selected from the group consisting of water, water miscibleorganic solvents and mixtures thereof to form mixture, to obtain an HANcompound of formula VI, wherein R₁ and R₂ are independently a C₁₋₆ alkylor a C₆₋₈ aryl.
 81. The method of claim 80, wherein R₁ and R₂ aremethyl.
 82. The method of claim 80, wherein the OAN salt is OAN-MsOH.83. The method of claim 80, wherein the water miscible organic solventis a C₁₋₄ alcohol.
 84. (canceled)
 85. The method of claim 80, whereinthe reducing reagent is a metal hydride complex.
 86. (canceled)
 87. Themethod of claim 80, wherein the mixture comprising the OAN salt, thewater miscible organic solvent, and the reducing agent is maintained ata temperature of about 25° C. to about 35° C.
 88. The method of claim80, further comprising recovering the HAN compound of formula VI. 89.(canceled)
 90. (canceled)
 91. The method of claim 80, further comprisingcombining the HAN compound of formula VI, an acid, and an organicsolvent selected from the group consisting of a C₁₋₄ alcohol, a C₂₋₈ester, a linear, branched or cyclic C₂₋₈ ether, a C₃₋₆ ketone, a C₅₋₈aliphatic hydrocarbon, a C₁₋₈ halogenated hydrocarbon, a C₁₋₄nitroalkane, a C₁₋₄ alkylcyanide, a C₆₋₈ aromatic hydrocarbon, a C₃₋₁₀amide, and mixtures thereof, forming a mixture to obtain a HAN-salt offormula VIs

wherein R₁ and R₂ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl and Z isan acid.
 92. (canceled)
 93. The method of claim 91, further comprisingadding a base, wherein the HAN compound of formula V is obtained as apurified compound.
 94. (canceled)
 95. (canceled)
 96. (canceled) 97.(canceled)
 98. A method of preparing a7-alkoxycarbonyl-9-(alkoxycarbonylmethyl)-3-trialkylsilyloxy-9-azabicyclo[3.3.1]nonanecompound (a SAN compound) of formula X

comprising combining a HAN-salt of formula VIs

a silylating agent selected from a group consisting of: silanes, silylhalogenides, silyl cyanides, silyl amines, silyl amides, silyltrifluoromethanesulfonates (silyl triflates), and silazanes, a base, andan aprotic organic solvent, forming a mixture to obtain the SAN compoundof formula X, wherein, R₁ and R₂ are independently C₁₋₆ alkyl or C₆₋₈aryl, and R₃R₄R₅ are independently C₁₋₆ alkyl or C₆₋₈ aryl, or R₃R₄R₅together are a tert-butyldialkyl, and Z is an acid.
 99. The method ofclaim 98, wherein R₁ and R₂ are methyl, R₃R₄R₅ together aretert-butyldimethyl.
 100. The method of claim 98, wherein the a-proticorganic solvent is selected from the group consisting of a C₁₋₈halogenated hydrocarbon, a C₂₋₈ ester, a C₂₋₈ ether, a C₆₋₈ aromatichydrocarbon, a C₃₋₁₀ amide, and a C₃₋₆ ketone.
 101. (canceled)
 102. Themethod of claim 98, wherein the amount of base is about 2 to about 10mole equivalent of base per mole equivalent of the HAN-salt.
 103. Themethod of claim 98, wherein the base is selected from the groupconsisting of: sodium hydroxide, sodium carbonate, sodium bicarbonate,potassium hydroxide, potassium carbonate potassium bicarbonate, trialkylamines, and N-containing heterocycles.
 104. (canceled)
 105. (canceled)106. The method of claim 98, wherein the base is added at a temperatureof about 15° C. to about 55° C.
 107. The method of claim 98, wherein thesilylating agent is selected from the group consisting oftriethylsilane, triisopropylsilane, and triphenylsilane.
 108. The methodof claim 98, wherein the silylating agent is trialkylsilyl halogenide.109. (canceled)
 110. The method of claim 108, wherein the silylatingagent is added in an amount of about 1 to about 4 mole equivalent ofsylilating agent per mole equivalent of the HAN-salt.
 111. The method ofclaim 98, wherein the mixture is maintained at a temperature of about20° C. to about 60° C.
 112. The method of claim 98, further comprisingrecovering SAN of formula X.
 113. (canceled)
 114. (canceled)
 115. Amethod of preparing anendo-9-alkoxycarbonyl-5-trialkylsilyloxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-onecompound (a SQO compound) of formula XII

comprising, a) mixing a SAN compound of formula X, a metal alkoxide, anda polar aprotic organic solvent to form a mixture; b) heating themixture; and c) reacting the heated mixture of step b) with a weak acid,forming-the SQO compound of formula XII, wherein, R is a C₁₋₆ alkyl or aC₆₋₈ aryl, and R₃R₄R₅ are independently a C₁₋₆ alkyl or a C₆₋₈ aryl, orR₃R₄R₅ together are a tert-butyldialkyl.
 116. The method of claim 115,wherein R is methyl and R₃R₄R₅ together are tert-butyldimethyl. 117.(canceled)
 118. The method of claim 115, wherein the polar a-proticorganic solvent is THF.
 119. The method of claim 115, wherein the metalalkoxide is selected from the group consisting of lithium alcoholates,sodium alcoholates and potassium alcoholates; wherein the alcoholatemoiety contains 1 to 4 carbons.
 120. (canceled)
 121. The method of claim115, wherein the mixture is heated to a temperature of about 40° C. toabout 120° C.
 122. The method of claim 121, wherein the heated mixtureis cooled to a temperature of about 0° C. to about 30° C.
 123. Themethod of claim 115, wherein the weak acid is selected from the groupconsisting of acetic acid, formic acid, propionic acid, maleic acid,fumaric acid, succinic acid, oxalic acid, tartaric acid, citric acid,mandelic acid, benzoic acid, salicylic acid, naphthalene carboxylic anddicarboxylic acids, methanesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, benzenesulfonic acid, naphthalene sulfonic and disulfonic acids124. The method of claim 123, wherein the acid is acetic acid. 125.(canceled)
 126. The method of claim 115, further comprising recoveringthe SQO compound of formula XII.
 127. (canceled)
 128. (canceled)
 129. Amethod of preparingendo-5-hydroxy-8-azatricyclo[5.3.1.0^(3,8)]undecan-10-one (HQO) offormula II

comprising mixing a SQO compound of formula XII, water or awater-miscible organic solvent, and an acid selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, perchloric acid, fluoroboric acid,methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonicacid, naphthalene sulfonic and disulfonic acids, to obtain the HQOcompound.
 130. The method of claim 129, wherein the water-miscibleorganic solvent is dimethylformamide, dimethylacetamide, dimethylsulfoxide, or diglyme.
 131. The method of claim 129, wherein the solventis water.
 132. The method of claim 129, wherein the SQO compound offormula XII is combined with the solvent at a temperature of about 10°C. to about 50° C.
 133. (canceled)
 134. The method of claim 129, whereinthe mixture is heated to a temperature of about 80° C. to about 100° C.135. The method of claim 129, further comprising recovering HQO offormula II.
 136. The method of claim 129, wherein HQO is preparedcomprising combining a SAN compound of formula X, in stead of the SQOcompound of formula XII.
 137. (canceled)
 138. The method of claim 129,further comprising combining HQO, an alcohol and an acid selected fromthe group consisting of: hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, perchloric acid, fluoroboric acid,formic acid, acetic acid, propionic acid, trichloroacetic acid,trifluoroacetic acid, maleic acid, fumaric acid, succinic acid, oxalicacid, tartaric acid, citric acid, mandelic acid, benzoic acid, salicylicacid, naphthalene carboxylic and dicarboxylic acids, methanesulfonicacid, ethanesulfonic acid, trifluoromethanesulfonic acid,p-toluenesulfonic acid, benzenesulfonic acid, naphthalene sulfonic, anddisulfonic acid to obtain a HQO salt of formula IIs.
 139. The method ofclaim 138, further comprising the step of adding a base to obtainpurified HQO.
 140. The method of claim 138, wherein the alcohol is aC₁₋₄ alcohol.
 141. (canceled)
 142. (canceled)
 143. (canceled) 144.(canceled)
 145. (canceled)
 146. (canceled)
 147. (canceled) 148.(canceled)
 149. (canceled)
 150. A method of preparing a Dolasetron saltof formula VIIIs, comprising a) combining a CCA-ester of formula III, anoxidizing agent selected from the group consisting of: hydroperoxides,dialkyl peroxides, peroxyacids, peroxyesters, diacyl peroxides,persulphate, perborate and perphosphate, a catalyst and a solventselected from the group consisting of water, water miscible organicsolvents and mixtures thereof, to form CCA-epoxide of formula IV; b)admixing CCA-epoxide with an oxidizing agent, and a solvent selectedfrom the group consisting of water and a water miscible organic solvent;c) raising the pH; d) admixing with a pH 4 buffer, a glycine C₁₋₄ esteror salts thereof, and a substance comprising a carbonyl moiety selectedfrom the group consisting of 1,3 acetonedicarboxylic acids, acetone anda C₁₋₄ ester thereof, to form OAN of formula V; e) admixing with areducing agent, and a solvent selected from the group consisting ofwater, water miscible organic solvents and mixtures thereof, to form HANof formula VI; f) admixing with a silylating agent selected from a groupconsisting of: silanes, silyl halogenides, silyl cyanides, silyl amines,silyl amides, silyl trifluoromethanesulfonates (silyl triflates), andsilazanes, a base, and an aprotic organic solvent to form SAN of formulaX; g) admixing with a metal alkoxide, and a polar a-protic organicsolvent to form a reaction mixture; h) heating the reaction mixture; i)quenching with a weak acid selected from the group consisting of aceticacid, formic acid, acetic acid, propionic acid, maleic acid, fumaricacid, succinic acid, oxalic acid, tartaric acid, citric acid, mandelicacid, benzoic acid, and salicylic acid forming SQO of formula XII; j)admixing with a solvent selected from a group consisting of: water, andwater-immiscible organic solvent, and an acid selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, perchloric acid, fluoroboric acid,methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonicacid, naphthalene sulfonic and disulfonic acids to form HQO of formulaII; k) admixing with an anhydride, 3-indole carboxylic acid, ahalogenated hydrocarbon, and a catalyst to obtain Dolasetron base; andl) reacting Dolasetron base with an acid to obtain the DLS-salt offormula VIIIs.